RU2833220C2 - Protein tyrosine phosphatase inhibitors and methods of use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to 5-{(7R)-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ⁶,2,5-thiadiazolidine-1,1,3-trione.

EFFECT: obtaining 5-{(7R)-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ⁶,2,5-thiadiazolidine-1,1,3-trione, having inhibitory activity with respect to protein tyrosine phosphatase of non-receptor type 2 (PTPN2) and/or protein tyrosine phosphatase of non-receptor type 1 (PTPN1).

3 cl, 6 tbl, 232 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of U.S. Provisional Application No. 62/818,447, filed March 14, 2019, the contents of which are incorporated herein by reference in their entirety.

PRIOR ART

[002] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (e.g., PD-1/PD-L1 and CTLA-4 blocking antibodies), have been shown to be effective in treating a variety of cancers, dramatically improving outcomes in some populations that are refractory to traditional treatments. However, incomplete clinical responses and the development of intrinsic or acquired resistance will continue to limit the patient populations that can benefit from checkpoint blockade.

[003] Protein tyrosine phosphatase nonreceptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 phosphotyrosine-specific phosphatases subfamily that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is expressed ubiquitously, but expression is highest 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 controlled by the existence of two splice variants: a 45 kDa form that contains a nuclear localization signal at the C-terminus before splicing, and a canonical 48 kDa form that has a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994). The 45 kDa isoform can be passively transfused into the cytosol under certain conditions of cellular stress. Both isoforms share a common N-terminal phosphotyrosine phosphatase catalytic domain. PTPN2 negatively regulates signaling of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a/b), and Src family kinases (e.g., Fyn, Lck). As a critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNγ. The catalytic domain of PTPN2 shares 74% sequence homology with PTPN1 (also called PTP1B) and has similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003).

[004] In vivo loss-of-function genetic screening data using CRISPR/Cas9 genome editing in the B16F10 mouse tumor transplant model show that deletion of the Ptpn2 gene in tumor cells improves response to a GM-CSF-secreting vaccine (GVAX) immunotherapy regimen 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 also depleted under selective immunotherapy pressure, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. These observations point to a putative role for therapeutic strategies that enhance IFNγ sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens.

[005] Protein tyrosine phosphatase nonreceptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play a key role in insulin and leptin signaling and is the primary mechanism for suppression of insulin and leptin receptor signaling (Kenner KA et al., J Biol Chem 271: 19810-19816, 1996). PTPN1-deficient animals have improved glucose regulation and lipid profiles and are resistant to weight gain when fed a high-fat diet (Elchebly M et al., Science 283: 1544-1548, 1999). Thus, PTPN1 inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome.

ESSENCE OF THE INVENTION

[006] The present disclosure is directed, at least in part, to compounds, compositions, and methods for inhibiting a protein tyrosine phosphatase, such as protein tyrosine phosphatase non-receptor type 2 (PTPN2) and/or protein tyrosine phosphatase non-receptor type 1 ((PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B)). In some embodiments, disclosed herein is an inhibitor of a protein tyrosine phosphatase, such as PTPN2 and/or PTPN1, comprising a compound disclosed herein. In other embodiments, disclosed herein are methods of treating a disease or disorder, such as cancer, type 2 diabetes, obesity, metabolic disease, or any other disease, disorder, or ailment that responds favorably to treatment with PTPN2 or PTPN1 inhibitors, comprising administering an effective amount of a compound described herein.

[007] For example, this document discloses a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Z is selected from the group consisting of C(H)(R ³ ), bond and N(R ⁸ );

R ¹ is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -OC _1-6 alkyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -OC _1-6 alkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ;

R ² is selected from the group consisting of hydrogen, -C _1-6 alkyl, -C _2-6 alkenyl, -OC _1-6 alkyl, -NH ₂ , -N(R ^a )-C _1-8 alkyl, -N(R ^a )-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ , -C _{1-6 alkylene} -N(R ^a )-C _1-6 alkyl, -C _1-6 alkylene-N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkylene-N(R ^a )(R ^b ), _-N (R ^a )-(C=N(R ^b ))-C _1-6 alkyl, -S(O) _w -C _1-6 alkyl, -C(O)-N(R ^a )-C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^a )-C _1-6 alkyl, -OC(O)-N(R ^a )-phenyl, -N(R ^a )-C(O)-OC _1-6 alkyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -N(R ^a )-4-6-membered heterocyclyl, -C _1-6 alkylene-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^a )-C _1-6 alkylene-phenyl;

where -C _1-6 alkyl, -C _2-6 alkenyl, -OC _1-6 alkyl, -N(R ^a )-C _1-8 alkyl, -N(R ^a )-C _3-6 cycloalkyl, -N (R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ , -C ₁ - ₆ alkylene-N(R ^a )-C _1-6 alkyl, -C ₁ - ₆ alkylene-N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-(C=N(R ^b ))-C _1-6 alkyl, -S(O) _w -C _1-6 alkyl, -C(O)-N(R ^a )-C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^a )-C _1-6 alkyl, -OC(O)-N(R ^a )-phenyl, -N(R ^a )-C(O)-OC _1-6 alkyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene-4-6 membered heterocyclyl, -OC _1-6 alkylene-4-6 membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4-6 membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^a )-C _1-6 alkylene-phenyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents, each independently selected from R ^g ;

wherein if the 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, -N(R ^a )-4- to 6-membered heterocyclyl, -C _1-6 alkylene-4- to 6-membered heterocyclyl, -OC _1-6 alkylene-4- to 6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4- to 6-membered heterocyclyl or -N(R ^a )-C _1-6 alkylene-5- to 6-membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with R ^h ; and

where if Z is C(H)(R ³ ), then R ² is not -CH ₂ -CH ₃ ;

R ^2' is selected from the group consisting of hydrogen, -NR ^a R ^b and -N(R ^a )-N(R ^b )-C(O)-phenyl;

R³selected from the group consisting of hydrogen, -C_1-6alkyl, -O-C_1-6alkyl, -O-C_1-6alkylene-C_3-6cycloalkyl, -N(R^a)-C_1-6alkyl, -N(R^a)-C_1-6alkylene-C₃-₆cycloalkyl, -S(O)_w-C_1-6alkyl, -C(O)-N(R^a)-C_1-6alkyl, -N(R^a)-C(O)-C_1-6alkyl and -C_1-6alkylene-4-6-membered heterocyclyl;

wherein _-C1-6 alkyl, _-OC1-6 alkyl, _{-OC1-6 alkylene} - _C3-6 cycloalkyl, -N(R ^a ) _-C1-6 alkyl, -N(R ^a ) _-C1-6 alkylene- _C3-6 cycloalkyl, -S(O) _w - _C1-6 alkyl, -C(O)-N(R ^a ) _-C1-6 alkyl, -N(R ^a )-C(O) _-C1-6 alkyl and _-C1-6 alkylene-4-6-membered heterocyclyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁴ is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁵ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁶ is selected from the group consisting of hydrogen and deuterium;

R ⁷ is selected from the group consisting of hydrogen and deuterium;

R ⁸ is selected from the group consisting of hydrogen and C _1-6 alkyl,

R ^g is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, R ^a R ^b N-, R ^a R ^b NC(O)-, R ^a R ^b N-SO _w -, R ^a R ^b NC(O)-N(R ^a )-, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkylene-, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^a )-, C _1-6 alkyl-N(R ^a )-C(O)-, C _1-6 alkyl-C(O)-N(R ^a ), C _1-6 alkyl-N(R ^a )-C(O)-N(R ^a )-, C _1-6 alkyl-N(R ^a )-SO _w -, C _3-6 cycloalkyl-N(R ^a )-SO _w -, C _1-6 alkyl-SO _w -N(R ^a )-, C _3-6 cycloalkyl-SO _w -N(R ^a )-, C _1-6 alkoxy-C(O)-N(R ^a )-, C _1-6 alkyl-C(O)-N(R ^a )-C _1-6 alkyl-, C _1-6 alkyl-N(R ^a )-C(O)-C _1-6 alkyl- and C _1-6 alkoxy-C _1-6 alkyl-; where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^a )-, C _1-6 alkyl-N(R ^a )-C(O)-, C _1-6 alkyl-C(O)-N(R ^a ), C _1-6 alkyl-N(R ^a )-C(O)-N(R ^a )-, _C1-6 alkyl-N(R ^a )-SO _w -, _C3-6 cycloalkyl-N(R ^a )-SO _w -, _C1-6 alkyl-SO _w -N(R ^a )-, _C3-6 cycloalkyl-SO _w -N(R ^a )-, _C1-6 alkoxy-C(O)-N(R ^a )-, _C1-6 alkyl-C(O)-N(R ^a ) _-C1-6 alkyl-, _C1-6 alkyl-N(R ^a )-C(O) _-C1-6 alkyl- and _C1-6 alkoxy- _C1-6 alkyl- may be optionally substituted with one, two, three or more substituents each independently selected from R ^P ;

R ^h is independently selected for each occurrence from the group consisting of C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)-, and R ^a R ^b N-SO ₂ -; wherein C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)- and R ^a R ^b N-SO ₂ - may optionally be substituted with one, two, three or more substituents, each of which is independently selected from R ^P ;

R ^P is independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, R ^a R ^b N-, R ^a R ^b N-carbonyl-, R ^a R ^b N-SO ₂ -, and R ^a R ^b N-carbonyl-N(R ^a )-;

R ^a and R ^b are independently selected for each occurrence from the group consisting of hydrogen and C _1-6 alkyl; wherein C _1-6 alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

or R ^a and R ^b together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

R ^c is independently selected for each occurrence from the group consisting of hydroxyl, C _1-4 alkyl, and phenyl; and

w is 0, 1, or 2.

[008] This document also discloses a compound represented by Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

X ^II1 is selected from the group consisting of O and C(R ^II1 )(R ^II1' );

X ^II4 is selected from the group consisting of O and C(R ^II4 )(R ^II4' );

where at least one of X ^II1 and X ^II4 is O;

R ^II1 and R ^II1' are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _3-6 cycloalkyl;

wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ;

R ^II2 is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, -N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -S(O) ₂ -C _1-6 alkyl, -C(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)-OC _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C _1-6 alkylene-4-6 membered heterocyclyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^IIa )-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^IIa )-C _1-6 alkylene-phenyl;

where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, -N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -S(O) ₂ -C _1-6 alkyl, -C(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)- OC _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C _1-6 alkylene-4-6-membered heterocyclyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -N (R ^IIa )-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^IIa )-C _1-6 alkylene-phenyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents, each of which is independently selected from R ^IIg ;

where, if 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-4-6 membered heterocyclyl, or -N(R ^IIa )-C _1-6 alkylene-5-6 membered heteroaryl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^IIh ; And

where if R ^II2 is -OC _1-6 alkyl, -N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -S(O ) ₂ -C _1-6 alkyl, -N(R ^IIa )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)-OC _1-6 alkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^IIa )-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-5-6-membered heteroaryl or -N(R ^IIa )-C _1-6 alkylene-phenyl; then X ^II1 is C(R ^II1 )(R ^II1' ) and X ^II4 is O;

R ^II2' is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-5-6-membered heteroaryl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, _-C1-6 alkylene- _C3-6 cycloalkyl, _-C1-6 alkylene-phenyl, _-C1-6 alkylene-5-6-membered heteroaryl and _-C1-6 alkylene-4-6-membered heterocyclyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ; and

wherein if the 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -C _1-6 alkylene-5-6 membered heteroaryl or -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^IIh ;

R ^II3 and R ^II3' are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _3-6 cycloalkyl;

wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ;

R ^II4 and R ^II4' are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _3-6 cycloalkyl;

wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ;

R ^II5 is selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl and C _3-6 cycloalkyl;

wherein C _1-6 alkyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ;

R ^II6 is selected from the group consisting of hydrogen and deuterium;

R ^II7 is selected from the group consisting of hydrogen and deuterium;

R ^IIg is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, R ^IIa R ^IIb N-, R ^IIa R ^IIb NC(O)-, R ^{IIa IIb} N-SO _w -, R ^IIa R ^IIb NC(O)-N(R ^IIIa )-, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkylene-, C _1-6 alkoxy, C _3-6 alkenyloxy, C _{3-6 alkynyloxy, C 3-6 cycloalkoxy} , C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^IIa )-, C _1-6 alkyl-N(R ^IIa )-C(O)-, C _1-6 alkyl-C(O)-N(R ^IIa ), C _1-6 alkyl-N(R ^IIa )-C(O)-N(R ^IIa )-, C _1-6 alkyl-N(R ^IIa )-SO _w -, C _3-6 cycloalkyl-N(R ^IIa )-SO _w -, C _1-6 alkyl-SO _w -N(R ^IIa )-, C _3-6 cycloalkyl-SO _w -N(R ^IIa )-, C _1-6 alkoxy-C(O)-N(R ^IIa )-, C _1-6 alkyl-C(O)-N(R ^IIa )-C _1-6 alkyl-, C _1-6 alkyl-N(R ^IIa )-C(O)-C _1-6 alkyl- and C _1-6 alkoxy-C _1-6 alkyl-; where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^IIa )-, C _1-6 alkyl-N(R ^IIa )-C(O)-, C _1-6 alkyl-C(O)-N(R ^IIa ), C _1-6 alkyl-N(R ^IIa) )-C(O)-N(R ^IIa )-, _C1-6 alkyl-N(R ^IIa ) _-SOw- , _C3-6 cycloalkyl-N(R ^IIa )-SOw-, _C1-6 alkyl-SOw _- N(R ^IIa )-, _C3-6 cycloalkyl-SOw _- N( _R ^IIa )-, _C1-6 alkoxy-C(O)-N(R ^IIa )-, _C1-6 alkyl-C(O)-N(R ^IIa ) _-C1-6 alkyl-, _C1-6 alkyl-N(R ^IIa )-C(O) _-C1-6 alkyl- and _C1-6 alkoxy- _C1-6 alkyl- may be optionally substituted with one, two, three or more substituents each independently selected from R ^IIP ;

R ^IIh is independently selected for each occurrence from the group consisting of C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^IIa R ^IIb NC(O)-, and R ^IIa R ^IIb N-SO ₂ -; wherein C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^IIa R ^IIb NC(O)- and R ^IIa R ^IIb N-SO ₂ - may be optionally substituted with one, two, three or more substituents, each of which is independently selected from R ^IIP ;

R ^IIP is independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, R ^IIa R ^IIb N-, R ^IIa R ^IIb N-carbonyl-, R ^IIa R ^IIb N-SO ₂ -, and R ^IIa R ^IIb N-carbonyl-N(R ^IIa )-;

R ^IIa and R ^IIb are independently selected for each occurrence from the group consisting of hydrogen and C _1-3 alkyl; wherein C _1-3 alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

or R ^IIa and R ^IIb together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and

w is 0, 1, or 2.

[009] The present document further discloses a compound represented by Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R ^III1 is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^III2 is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl, 4-7-membered heterocyclyl, 5-6-membered heteroaryl, -C _1-6 alkylene-C _3-8 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-4-7-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C(O)-C _1-6 alkyl, _-C ⁽ O)-OC _1-6 alkyl, -C(O)-C _1-6 alkylene-C _3-8 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-phenyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-4-7-membered heterocyclyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-5-6-membered heteroaryl, -C=N(R ^IIIa )-C _1-6 alkyl and -S(O) ₂ -C _1-6 alkyl;

where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl, 4-7-membered heterocyclyl, 5-6-membered heteroaryl, -C _1-6 alkylene-C _3-8 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-4-7-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C(O)-C _1-6 alkyl, -C(O)-OC _1-6 alkyl, -C(O)-C _1-6 alkylene-C _3-8 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-phenyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-4-7-membered heterocyclyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-5-6-membered heteroaryl, -C=N(R ^IIIa )-C _1-6 alkyl and -S(O) ₂ -C _1-6 alkyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIIg ; and

where, if 4-7-membered heterocyclyl, 5-6-membered heteroaryl, -C _1-6 alkylene-4-7-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C(O) -N(R ^IIIa )-C _1-6 alkylene-4-7-membered heterocyclyl or -C(O)-N(R ^IIIa )-C _1-6 alkylene 5-6 membered heteroaryl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^IIIh ;

R ^III3 is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^III4 is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^III4' is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^III5 is selected from the group consisting of hydrogen, halogen and C _1-6 alkyl;

R ^III6 is selected from the group consisting of hydrogen and deuterium;

R ^III7 is selected from the group consisting of hydrogen and deuterium;

R ^IIIg is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, R ^IIIa R ^IIIb N-, R ^IIIa R ^IIIb NC(O)-, R ^{IIIa IIIb} N-SO _w -, R ^IIIa R ^IIIb NC(O)-N(R ^IIIa )-, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkylene-, C _1-6 alkoxy, C _3-6 alkenyloxy, C _{3-6 alkynyloxy, C 3-6 cycloalkoxy} , C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^IIIa )-, C _1-6 alkyl-N(R ^IIIa )-C(O)-, C _1-6 alkyl-C(O)-N(R ^IIIa ), C _1-6 alkyl-N(R ^IIIa )-C(O)-N(R ^IIIa )-, C _1-6 alkyl-N(R ^IIIa )-SO _w -, C _3-6 cycloalkyl-N(R ^IIIa )-SO _w -, C _1-6 alkyl-SO _w -N(R ^IIIa )-, C _3-6 cycloalkyl-SO _w -N(R ^IIIa )-, C _1-6 alkoxy-C(O)-N(R ^IIIa )-, C _1-6 alkyl-C(O)-N(R ^IIIa )-C _1-6 alkyl-, C _1-6 alkyl-N(R ^IIIa )-C(O)-C _1-6 alkyl-, C _1-6 alkoxy-C _1-6 alkyl- and 5-6-membered heteroaryl; where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^IIIa )-, C _1-6 alkyl-N(R ^IIIa )-C(O)-, C _1-6 alkyl-C(O)-N(R ^IIIa ), C _1-6 alkyl-N(R ^IIIa) )-C(O)-N(R ^IIIa )-, _C1-6 alkyl-N(R ^IIIa ) _-SOw- , _C3-6 cycloalkyl-N(R ^IIIa )-SOw-, _C1-6 alkyl-SOw _- N(R ^IIIa )-, _C3-6 cycloalkyl-SOw _- N( _R ^IIIa )-, _C1-6 alkoxy-C(O)-N(R ^IIIa )-, _C1-6 alkyl-C(O)-N(R ^IIIa ) _-C1-6 alkyl-, _C1-6 alkyl-N(R ^IIIa )-C(O) _-C1-6 alkyl-, _C1-6 alkoxy- _C1-6 alkyl- and 5-6-membered heteroaryl may be optionally substituted with one, two, three or more substituents each independently selected from R ^IIIP ;

R ^IIIh is independently selected for each occurrence from the group consisting of C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^IIIa R ^IIIb NC(O)-, R ^IIIa R ^IIIb N-SO ₂ - and -C _1-6 alkylene-5-6-membered heteroaryl; wherein C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^IIIa R ^IIIb NC(O)-, R ^IIIa R ^IIIb N-SO ₂ - and -C _1-6 alkylene-5-6-membered heteroaryl may be optionally substituted with one, two, three or more substituents each independently selected from R ^IIIP ;

R ^IIIP for each occurrence is independently selected from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, R ^IIIa R ^IIIb N-, R ^IIIa R ^IIIb N-carbonyl-, R ^IIIa R ^IIIb N-SO ₂ - and R ^IIIa R ^IIIb N-carbonyl-N(R ^IIIa )-;

R ^IIIa and R ^IIIb are independently selected for each occurrence from the group consisting of hydrogen and C _1-3 alkyl; wherein C _1-3 alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

or R ^IIIa and R ^IIIb together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and

w is 0, 1, or 2.

[0010] The present document further discloses a compound selected from the group consisting of:

5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin-1,1,3- trion;

5-[(7 R )-1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(7 S )-1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(5-fluoro-7-hydroxy-3,4-dihydro-2 H -1-benzopyran-6-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(5-fluoro-7-hydroxy-2,2-dimethyl-3,4-dihydro-2 H -1-benzopyran-6-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2,2-dimethyl-3,4-dihydro-2 H -1-benzopyran-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1,4-difluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalene-2-yl)-1λ ^6,2,5 -thiadiazolidine-1,1,3-trione;

5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 S )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin-1, 1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4-methoxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5- thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3-methoxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2,2-difluoro-2-phenylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(3-cyclopropyl-2,2-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ⁶ 2,5-thiadiazolidine -1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[methyl(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin-1,1 ,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4-methylpentyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[4,4,4-trifluoro-3-(trifluoromethyl)butyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 S )-7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[2-(pyridin-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 RS )-1-fluoro-3-hydroxy-7-[(3 RS )-pyrrolidin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 RS )-7-[(3 RS )-1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 RS )-1-fluoro-3-hydroxy-7-[(3 SR )-pyrrolidin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 RS )-7-[(3 SR )-1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[2-(1 H -pyrazol-1-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(4-methylpentanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(4-methylpentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 S )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(7 R )-1-fluoro-3-hydroxy-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl phenylcarbamate;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ^6,2,5 -thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene-2-yl ]amino}-2,2-dimethylbutanenitrile;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3-hydroxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3-methoxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(5,5,5-trifluoropentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ^6,2,5 -thiadiazolidin-1,1 ,3-trione;

5-(1-fluoro-3-hydroxy-7-{(3-methylbutyl)[(pyridin-2-yl)methyl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl)-1λ ⁶ , 2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[(pyridin-2-yl)methyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-2-hydroxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(7-{[2-(difluoromethoxy)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-pentanimidoyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(3-cyclopropylpropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(2-azaspiro[3.3]heptan-6-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ^6,2,5 -thiadiazolidine -1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(6,6,6-trifluorohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(3,3-difluorocyclobutyl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(azetidin-3-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[(propan-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(azetidin-3-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(azetidin-3-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{(3-methylbutyl)[2-(pyridin-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[(spiro[2.3]hexan-5-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[2-(trifluoromethoxy)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3-hydroxy-3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

3-hydroxybutyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate;

5-{1-fluoro-3-hydroxy-7-[3-(propan-2-yl)pyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclohexylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-(butylamino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 S )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclopentylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(2-cyclohexylethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(2-hydroxyethyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(2 R )-2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[(pyrrolidin-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[(pyridin-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclobutylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(2-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclopropyl-2-hydroxyethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[3-(trimethylsilyl)propyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({3-[hydroxy(dimethyl)silyl]propyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,3-difluorocyclobutyl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N -[8-fluoro-6-hydroxy-7-(1,1,4-trioxo- ^1λ 6,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene-2-yl] -3-methylbutanimidamide;

5-{8-fluoro-6-hydroxy-2-[3-(oxan-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(7 R )-7-amino-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(4,4-difluorobutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(2-cyclopentylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{( 7R )-7-[(2-cyclobutylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl} ^-1λ6,2,5 -thiadiazolidine -1,1,3-trione;

5-[(7 R )-7-{[2-(3,3-difluorocyclobutyl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(3-methylpentyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(3-ethylpentyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

8-fluoro-6-hydroxy- N -(3-methylbutyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(2-methylpropyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-{8-fluoro-6-hydroxy-2-[3-(pyridin-3-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(1,3,5-trimethyl-1 H -pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(pyrimidin-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(3,5-dimethyl-1 H -pyrazol-4-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[(1,3,5-trimethyl-1 H -pyrazol-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(oxan-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(2-cyclohexyl-2-hydroxyethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3-methoxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(3-aminopropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[3-(piperidin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

tert -butyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate;

5-{8-fluoro-6-hydroxy-2-[(7-oxabicyclo[2.2.1]heptan-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{1-[(1,3,5-trimethyl-1 H -pyrazol-4-yl)methyl]azetidin-3-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(7-oxabicyclo[2.2.1]heptan-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1 H -pyrazol-4-yl]ethyl}-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]methyl}-3,5-dimethyl-1 H -pyrazol-1-yl)-2,2-dimethylpentanenitrile;

5-{8-fluoro-6-hydroxy-2-[(piperidin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[3-(morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(piperidin-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[(1 s ,3 r )-3-(trifluoromethoxy)cyclobutyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[3-(4-methylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[(propan-2-yl)oxy]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({2-[(1 s ,3 r )-3-(trifluoromethoxy)cyclobutyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[(1 s ,3 s )-3-(trifluoromethoxy)cyclobutyl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{1-[(1,3,5-trimethyl-1 H -pyrazol-4-yl)methyl]piperidin-4-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[(1,3,5-trimethyl-1 H -pyrazol-4-yl)methyl]-2-azaspiro[3.3]heptan-6-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(2-{2-[1-(difluoromethyl)-3,5-dimethyl-1 H -pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(bicyclo[2.2.1]heptan-1-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-amino-1-fluoro-3-hydroxy-7-(prop-2-en-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N '-[8-fluoro-6-hydroxy-2-propyl-7-(1,1,4-trioxo- ^1λ 6,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene -2-yl]benzohydrazide;

5-[8-fluoro-6-hydroxy-2-(3-hydroxybutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(2 S )-2-aminopropyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(2 R )-2-aminopropyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(piperazin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{[ rac -(1 R ,2 R )-2-(pyridin-4-yl)cyclopropyl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(2-cyclopentyl-2-methoxyethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(2 R )-2-amino-4-cyclohexylbutanoyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{3-[(propan-2-yl)oxy]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(1-methyl-1 H -pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1 H -pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-amino-1-fluoro-3-hydroxy-7-(4-methylpentyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(7-amino-1-fluoro-3-hydroxy-7-propyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(1,3-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(1,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N -(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-{(7 S )-7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

8-fluoro-6-hydroxy- N -[(oxan-4-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[(3,3-difluorocyclobutyl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -[(oxolan-2-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -(2-cyclopropylethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[(1,3-dimethyl-1 H -pyrazol-5-yl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-{2-[2-(1- tert -butyl-3,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(aminomethyl)-4-fluoro-6-hydroxy-2,3-dihydro- 1H -inden-5-yl]-1λ ^6,2,5 -thiadiazolidine-1,1,3-trione;

5-(4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl)-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-(2-{[bis(3-methylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro- 1H -inden-5-yl)-1λ ^6,2,5 -thiadiazolidine -1,1,3-trione;

8-fluoro-6-hydroxy- N -[(oxolan-3-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[(1,5-dimethyl-1 H -pyrazol-4-yl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -[(1-methyl-1 H -pyrazol-5-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-(2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H - pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(2-{[(3-cyclopropylpropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro- 1H -inden-5-yl)-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-(4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl)-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-{2-[2-(1-ethyl-3,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N -(2,2-dimethylpropyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(3-methoxypropyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(3-methoxy-2,2-dimethylpropyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[2-(dimethylamino)ethyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -[2-(1-methylcyclopropyl)ethyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(2-methoxyethyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -[(oxetan-3-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(2-phenylethyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[3-(dimethylamino)propyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-[2-(3-cyclohexylpropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(7-{[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[3-(2,2-dimethylcyclopropyl)propyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-[(3 S )-5-fluoro-7-hydroxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(7-{[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(2 R )-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl]-1λ ^6.2 ,5-thiadiazolidine-1,1,3-trione;

5-[( 2S )-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl]-1λ ^6.2 ,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(4-methoxybutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{3-[3-(trifluoromethyl)phenyl]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-methyl-3-[4-(propan-2-yl)phenyl]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[4-(5,5-dimethyl-1,3-dioxan-2-yl)butyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-pentyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-2-[3-(4-fluorophenyl)propyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

tert -butyl [(1 r ,4 r )-4-{2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl) -3,4-dihydroisoquinolin-2( 1H )-yl]ethyl}cyclohexyl]carbamate;

5-{2-[3-(4- tert -butylphenyl)propyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3,5,5-trimethylhexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-2-[3-(2-fluorophenyl)propyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

3-hydroxybutyl 4,4,8-trifluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate;

5-(2-{[(2-cyclobutylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1 H -inden-5-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(7 R )-1-fluoro-3-hydroxy-7-{[(3 R )-3-hydroxybutyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(4-hydroxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-6-(3-hydroxy-3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[6-(cyclopropylmethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{6-[(4,4-difluorobutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[6-(4,4-difluorobutoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-6-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-6-(3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-6-[(3-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

tert -butyl (2-{[5-fluoro-7-hydroxy-6-(1,1,4-trioxo- ^1λ 6,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene -2-yl]oxy}ethyl)carbamate;

5-(1-fluoro-3-hydroxy-6-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{6-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin-1,1,3- trion;

5-[6-(2-aminoethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N -(cyclohexylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide;

5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{[(2 S )-5-oxopyrrolidin-2-yl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(3 S )-5-fluoro-7-hydroxy-3-(4-methylpentyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

and its pharmaceutically acceptable salt.

[0011] In some embodiments, a compound disclosed herein is formulated as a pharmaceutically acceptable composition comprising the disclosed compound and a pharmaceutically acceptable carrier.

[0012] Also disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound described herein in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

[0013] For example, disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein.

[0014] Additionally, the present document provides a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient an effective amount of a compound described herein.

[0015] This document, for example, describes a method for treating and/or controlling obesity in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein.

[0016] For example, a method for suppressing further weight gain in an overweight or obese patient in need thereof is disclosed herein, comprising administering to the patient an effective amount of a compound disclosed herein.

[0017] Also disclosed herein is a method for treating a metabolic disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein.

[0018] In some embodiments, the method includes treating a cancer. In some embodiments, the cancer includes pancreatic cancer, breast cancer, multiple myeloma, melanoma, or secretory cell cancer. In some embodiments, the method includes treating a metabolic disease. In some embodiments, the metabolic disorder includes nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Sayre disease.

[0019] Also disclosed herein is a composition for use in treating cancer in a patient in need thereof, wherein the composition comprises a compound disclosed herein in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

[0020] For example, disclosed herein is a composition for use in treating cancer in a patient in need thereof, the composition comprising a compound disclosed herein.

[0021] Also provided herein is a composition for use in treating type 2 diabetes in a patient in need thereof, the composition comprising a compound disclosed herein.

[0022] Disclosed herein, for example, is a composition for use in treating and/or controlling obesity in a patient in need thereof, wherein the composition comprises a compound disclosed herein.

[0023] For example, a composition for use in inhibiting further weight gain in an overweight or obese patient in need thereof is disclosed herein, the composition comprising a compound disclosed herein.

[0024] Also disclosed herein is a composition for use in treating a metabolic disease in a patient in need thereof, the composition comprising a compound disclosed herein.

[0025] In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, melanoma, or secretory cell cancer. In some embodiments, the metabolic disorder comprises nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Sayre disease.

SEQUENCE LISTING SUMMARY

[0026] Incorporated herein by reference in its entirety is a sequence listing entitled "CLS-016WO SEQ ID List_ST25.txt" containing SEQ ID NO: 1 through SEQ ID NO: 3, which includes the amino acid sequences disclosed herein. The sequence listing was provided in ASCII text format via EFS. The sequence listing was first generated on February 19, 2020 and is 7256 bytes in size.

DETAILED DESCRIPTION

[0027] The present disclosure is directed, at least in part, to compounds, compositions, and methods for inhibiting a protein tyrosine phosphatase, such as protein tyrosine phosphatase non-receptor type 2 (PTPN2) and/or protein tyrosine phosphatase non-receptor type 1 ((PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B)).

Definitions

Chemical definitions

[0028] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics , ^75th Ed., inside front cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry as well as specific functional groups and reactivity are described in Thomas Sorrell, Organic Chemistry , University Science Books, Sausalito, 1999; Smith and March, March 's Advanced Organic Chemistry , ^5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , ^3rd Edition, Cambridge University Press, Cambridge, 1987.

[0029] The abbreviations used herein have their usual meanings in the fields of chemistry and biology. The chemical structures and formulas given herein are constructed in accordance with the standard rules of chemical valence known in the chemical field.

[0030] The compounds described herein may contain one or more asymmetric centers and thus may exist in different isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers can be separated from the mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al. , Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The description further covers the compounds described herein as individual isomers substantially free of other isomers and, alternatively, as mixtures of different isomers.

[0031] As used herein, an enantiomeric pure compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess over the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound comprises greater than 75 wt.%, greater than 80 wt.%, greater than 85 wt.%, greater than 90 wt.%, greater than 91 wt.%, greater than 92 wt.%, greater than 93 wt.%, greater than 94 wt.%, greater than 95 wt.%, greater than 96 wt.%, greater than 97 wt.%, greater than 98 wt.%, greater than 99 wt.%, greater than 99.5 wt.%, or greater than 99.9 wt.%. enantiomer. In some embodiments, the masses are based on the combined mass of all enantiomers or stereoisomers of the compound.

[0032] In the compositions provided herein, the enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R compound. In some embodiments, the enantiomerically pure R compound in such compositions can, for example, comprise at least about 95% by weight of the R compound and a maximum of about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S compound. In some embodiments, the enantiomerically pure S compound in such compositions can, for example, comprise at least about 95% by weight of the % of the S-compound and at most about 5 wt. % of the R-compound, based on the total weight of the compound. In some embodiments, the active ingredient may be formulated with little or no filler or carrier.

[0033] "Isotopically enriched variant" as used herein refers to a disclosed compound having one or more isotopic substitutions, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that may be included in compounds according to the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus ^, sulfur, fluorine, and chlorine, such as ^2H , ^3H , ^13C , ^14C , 15N, 18O, ^17O , ^31P , ^32P , ^{35S , 18F} , and ^36Cl , respectively. For example, hydrogen (H) may be in any isotopic form, including ^1H , ^2H (D or deuterium), and ^3H (T or tritium); carbon (C) may be in any isotopic form, including ^12C , ^13C , and ^14C ; oxygen (O) may be in any isotopic form, including ^16O and ^18O ; and the like. For example, an isotopically enriched variant as disclosed herein may have one or more hydrogen atoms replaced with deuterium.

[0034] The singular forms may be used in this document to refer to one or more than one (i.e., at least one) grammatical objects of an entry. For example, "analog" means one analog or more than one analog.

[0035] When a range of values is specified, it is intended to encompass each value and subrange within the range. For example, the term " _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.

[0036] The following terms have the meanings set forth in conjunction with them below and are useful in understanding the description and intended scope of the present description.

[0037] “Alkyl” refers to a radical of a linear or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C ₁ -C ₂₀ alkyl”). In some embodiments, the alkyl group comprises from 1 to 12 carbon atoms (“C ₁ -C ₁₂ alkyl”). In some embodiments, the alkyl group comprises from 1 to 8 carbon atoms (“C ₁ -C ₈ alkyl”). In some embodiments, the alkyl group comprises from 1 to 6 carbon atoms (“C ₁ -C ₆ alkyl”). In some embodiments, the alkyl group comprises from 1 to 5 carbon atoms (“C ₁ -C ₅ alkyl”). In some embodiments, the alkyl group comprises from 1 to 4 carbon atoms (“C ₁ -C ₄ alkyl”). In some embodiments, the alkyl group comprises from 1 to 3 carbon atoms (“C ₁ -C ₃ alkyl”). In some embodiments, the alkyl group contains 1 to 2 carbon atoms (“C ₁ -C ₂ alkyl”). In some embodiments, the alkyl group contains 1 carbon atom (“C ₁ alkyl”). In some embodiments, the alkyl group contains 2 to 6 carbon atoms (“C ₂ -C ₆ alkyl”). Examples of C ₁ -C ₆ alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl (C ₄ ), sec-butyl (C ₄ ), iso-butyl (C ₄ ), n-pentyl (C ₅ ), 3-pentanyl (C ₅ ), amyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butanyl (C ₅ ), tertiary amyl (C ₅ ), and n-hexyl (C ₆ ). Further examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, from 1 to 5 substituents, from 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is unsubstituted C _1-10 alkyl (e.g., -CH ₃ ). In some embodiments, the alkyl group is substituted C _1-6 alkyl. Common abbreviations for alkyls include Me (-CH ₃ ), Et (-CH ₂ CH ₃ ), iPr (-CH(CH ₃ ) ₂ ), nPr (-CH ₂ CH ₂ CH ₃ ), n-Bu (-CH ₂ CH ₂ CH ₂ CH ₃ ), or i-Bu (-CH ₂ CH(CH ₃ ) ₂ ).

[0038] The term "alkylene" by itself or as part of another substituent _means , unless otherwise indicated, a divalent radical derived from alkyl, as exemplified, but not limited _to , _{-CH2CH2CH2CH2-} . Typically, an alkyl (or _alkylene ) group will have from 1 to 24 carbon atoms, with groups containing 10 or fewer carbon atoms being preferred herein. The term "alkenylene" by itself or as part of another substituent means, unless otherwise indicated, a divalent radical derived from an alkene. An alkylene group may be described, for example, as a _C1 - _C6 membered alkylene, where the term "membered" refers to the non-hydrogen atoms within the moiety.

[0039] “Alkenyl” refers to a straight or branched chain hydrocarbon radical having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds (“C ₂ -C ₂₀ alkenyl”). In some embodiments, an alkenyl group has from 2 to 10 carbon atoms (“C ₂ -C ₁₀ alkenyl”). In some embodiments, an alkenyl group has from 2 to 8 carbon atoms (“C ₂ -C ₈ alkenyl”). In some embodiments, an alkenyl group has from 2 to 6 carbon atoms (“C ₂ -C ₆ alkenyl”). In some embodiments, an alkenyl group has from 2 to 5 carbon atoms (“C ₂ -C ₅ alkenyl”). In some embodiments, an alkenyl group has from 2 to 4 carbon atoms (“C ₂ -C ₄ alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C ₂ -C ₃ alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C ₂ alkenyl"). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C ₂ -C ₄ alkenyl groups include ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), and the like. Examples of _C2 - _C6 alkenyl groups include the aforementioned _C2-4 alkenyl groups, as well as pentenyl ( _C5 ), pentadienyl ( _C5 ), hexenyl ( _C6 ), and the like. Further examples of alkenyl include heptenyl ( _C7 ), octenyl ( _C8 ), octatrienyl ( _C8 ), and the like. Each instance of an alkenyl group can be independently optionally substituted, e.g., unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl"), with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkenyl group is an unsubstituted _C2-10 alkenyl. In some embodiments, the alkenyl group is a substituted _C2-6 alkenyl.

[0040] "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 π-electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system (" _C6 - _C14aryl "). In some embodiments, the aryl group has six ring carbon atoms (" _C6aryl "; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms (" _C10aryl "; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (" _C14aryl "; e.g., anthracyl). An aryl group can be described, for example, as a _C6 - _C10 membered aryl, wherein the term "membered" refers to non-hydrogen ring atoms within the moiety. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group can be independently optionally substituted, for example, unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl"), with one or more substituents. In some embodiments, the aryl group is an unsubstituted _C6 - _C14 aryl. In some embodiments, the aryl group is a substituted _C6 - _C14 aryl.

[0041] In some embodiments, the aryl group is substituted with one or more groups selected from halogen, _C1 - _C8 alkyl, halo- _C1 - _C8 alkyl, halooxy- _C1 - _C8 alkyl, cyano, hydroxy, alkoxy _C1 - _C8 alkyl, and amino.

[0042] Examples of typical substituted aryls include the following

wherein one of R ⁵⁶ and R ⁵⁷ may be hydrogen, and at least one of R ⁵⁶ and R ⁵⁷ is each independently selected from C ₁ -C ₈ alkyl, halo-C ₁ -C ₈ alkyl, 4- to 10-membered heterocyclyl, alkanoyl, alkoxy-C ₁ -C ₈ alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR ⁵⁸ COR ⁵⁹ , NR ⁵⁸ SOR ⁵⁹ NR ⁵⁸ SO ₂ R ⁵⁹ , C(O)Oalkyl, C(O)Oaryl, CONR ⁵⁸ R ⁵⁹ , CONR ⁵⁸ OR ⁵⁹ , NR ⁵⁸ R ⁵⁹ , SO ₂ NR ⁵⁸ R ⁵⁹ , S-alkyl, S(O)-alkyl, S(O) ₂ -alkyl, S-aryl, S(O)-aryl, S( _O2 )-aryl; or R ⁵⁶ and R ⁵⁷ may be joined to form a cyclic ring (saturated or unsaturated) of 5-8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S.

[0043] Other typical aryl groups containing a fused heterocyclyl group include the following:

wherein each W' is selected from C(R ⁶⁶ ) ₂ , NR ⁶⁶ , O, and S; and each Y' is selected from carbonyl, NR ⁶⁶ , O, and S; and R ⁶⁶ is independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10-membered heterocyclyl, C ₆ -C ₁₀ aryl, and 5-10-membered heteroaryl.

[0044] “Arylene” and “heteroarylene” by themselves or as part of another substituent mean a divalent radical derived from aryl and heteroaryl, respectively. Non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl or quinolyl. The above examples may be substituted or unsubstituted, and the divalent radicals of each of the above heteroaryl examples are non-limiting examples of heteroarylene.

[0045] "Halo" or "halogen," independently or as part of another substituent, means, unless otherwise specified, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide," alone or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom. In some embodiments, the halogen group is fluorine or chlorine.

[0046] Furthermore, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-C ₁ -C ₆ alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0047] The term "heteroalkyl" by itself or in combination with another term means, unless otherwise indicated, a non-cyclic stable straight or branched chain or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and in which the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S and Si may be placed at any internal position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples of heteroalkyl groups include, but are not limited to: -CH2 _{-CH2 -O} - _CH3 , -CH2 _{-CH2 -NH} - _CH3 , _{-CH2 -CH2} -N( _CH3 ) _-CH3 , _-CH2 -S- _{CH2 -CH3} , -S(O) _-CH3 , -S(O) ₂ - _CH3 , _{-CH2 -CH2} -S(O) ₂ - _CH3 , -CH=CH-O- _CH3 , -Si( _CH3 ) ₃ , _-CH2 -CH=N- _OCH3 , -CH=CH-N( _CH3 ) _-CH3 , -O- _CH3 , and -O- _{CH2 -CH3} . Up to two or three heteroatoms may be consecutive, such as -CH2 _- NH- _OCH3 and _-CH2 -O-Si( _CH3 ) ₃ . When "heteroalkyl" is spoken followed by a listing of specific heteroalkyl groups such as _-CH2O - _CH3 , ^{-NRBRC ,} and the like, it is to be understood that the terms heteroalkyl and _-CH2O - _CH3 ^{or -NRBRC are} not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are listed for clarity. Thus, the term "heteroalkyl" should not be interpreted herein to exclude specific heteroalkyl groups such as _-CH2O - _CH3 , ^{-NRBRC ,} or the like.

[0048] Similarly, the term "heteroalkylene" by itself or as part of another substituent means, unless otherwise indicated, _{a divalent radical derived from heteroalkyl, as exemplified, but not limited to, -CH2O- and -CH2CH2O- . A} heteroalkylene group may be described, for example, as a 2-7 membered heteroalkylene, where the term "-membered" refers to the non-hydrogen atoms within the moiety. For heteroalkylene groups, the heteroatoms may also occupy one or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Additionally, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -C(O) ₂ R'- can be represented as -C(O) ₂ R'- and -R'C(O) ₂ -.

[0049] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms present in the aromatic ring system, wherein each heteroatom is 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 may be a carbon or nitrogen atom, if valence permits. Heteroarylbicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, wherein the point of attachment is on either the aryl or heteroaryl ring, and in such cases the number of ring members denotes the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (For example, indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on any ring,that ison a ring containing a heteroatom (For example, 2-indolyl), or a ring not containing a heteroatom (For example, 5-indolyl). A heteroaryl group may be described, for example, as a 6- to 10-membered heteroaryl, where the term "-membered" refers to the non-hydrogen ring atoms within the moiety.

[0050] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system comprising carbon ring atoms and 1-4 ring heteroatoms present in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system comprising carbon ring atoms and 1-4 ring heteroatoms present in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system comprising ring carbon atoms and 1-4 ring heteroatoms present in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl"), with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0051] Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0052] Examples of typical heteroaryls include the following formulas:

wherein each Y is selected from carbonyl, N, NR ⁶⁵ , O, and S; and R ⁶⁵ is independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl.

[0053] "Cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (" _C3 - _C10 cycloalkyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has from 3 to 8 ring carbon atoms (" _C3 - _C8 cycloalkyl"). In some embodiments, a cycloalkyl group has from 3 to 6 ring carbon atoms (" _C3 - _C6 cycloalkyl"). In some embodiments, a cycloalkyl group has from 3 to 6 ring carbon atoms (" _C3 - _C6 cycloalkyl"). In some embodiments, a cycloalkyl group has from 5 to 10 ring carbon atoms (" _C5 - _C10 cycloalkyl"). A cycloalkyl group may be described, for example, as a _C4 - _C7 -membered cycloalkyl, where the term "membered" refers to the non-hydrogen ring atoms within the moiety. Examples of _C3 - _C6 cycloalkyl groups include, without limitation, cyclopropyl ( _C3 ), cyclopropenyl ( _C3 ), cyclobutyl ( _C4 ), cyclobutenyl ( _C4 ), cyclopentyl ( _C5 ), cyclopentenyl ( _C5 ), cyclohexyl ( _C6 ), cyclohexenyl ( _C6 ), cyclohexadienyl ( _C6 ), and the like. Examples of _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. Examples of _C3 - _C10 cycloalkyl groups include, without limitation, the aforementioned _C3 - _C8 cycloalkyl groups, as well as cyclononyl ( _C9 ), cyclononenyl ( _C9 ), cyclodecyl ( _C10 ), cyclodecenyl ( _C10 ), octahydro- 1H -indenyl ( _C9 ), decahydronaphthalenyl ( _C10 ), spiro[4.5]decanyl ( _C10 ), and the like. As the above examples illustrate, in some embodiments, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or comprises a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic cycloalkyl"), and may be saturated or may be partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups, wherein the point of attachment is on the cycloalkyl ring, in which cases the number of carbon atoms continues to indicate the number of carbon atoms in the cycloalkyl ring system. Each instance of a cycloalkyl group may independently be optionally substituted, for example, unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl"), with one or more substituents. In some embodiments, a cycloalkyl group is an unsubstituted C ₃ -C ₁₀ cycloalkyl. In some embodiments, a cycloalkyl group is a substituted C ₃ -C ₁₀ cycloalkyl.

[0054] In some embodiments, "cycloalkyl" is a monocyclic saturated cycloalkyl group having from 3 to 10 ring carbon atoms (" _C3 - _C10 cycloalkyl"). In some embodiments, the cycloalkyl group has from 3 to 8 ring carbon atoms (" _C3 - _C8 cycloalkyl"). In some embodiments, the cycloalkyl group has from 3 to 6 ring carbon atoms (" _C3 - _C6 cycloalkyl"). In some embodiments, the cycloalkyl group has from 5 to 6 ring carbon atoms (" _C5 - _C6 cycloalkyl"). In some embodiments, the cycloalkyl group has from 5 to 10 ring carbon atoms (" _C5 - _C10 cycloalkyl"). 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 noted, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In some embodiments, a cycloalkyl group is an unsubstituted _C3 - _C10 cycloalkyl. In some embodiments, a cycloalkyl group is a substituted _C3 - _C10 cycloalkyl.

[0055] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and from 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, if valence permits. A heterocyclyl group may be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include 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 wherein the point of attachment is on either the cycloalkyl or heterocyclyl ring, or in ring systems wherein a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups wherein the point of attachment is on the heterocyclyl ring, in which cases the number of ring members continues to denote the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, wherein the term "-membered" refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus and silicon, within the group. Each instance of heterocyclyl may be independently optionally substituted, e.g., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl"), with one or more substituents. In some embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0056] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system comprising carbon ring atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system comprising carbon ring atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system comprising carbon ring atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0057] Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiorenyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Examples of 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Typical 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Typical 5-membered heterocyclyl groups fused to a _C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Typical 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0058] Specific examples of heterocyclyl groups are shown in the following illustrative examples:

wherein each W″ is selected from CR ⁶⁷ , C(R ⁶⁷ ) ₂ , NR ⁶⁷ , O, and S; and each Y″ is selected from NR ⁶⁷ , O, and S; and R ⁶⁷ is independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl ( e.g. amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O) ₂ -alkyl, -S(O) ₂ -aryl. Substituent groups include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

[0059] "Nitrogen-containing heterocyclyl group" means a 4-7 membered non-aromatic cyclic 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.

[0060] "Amino" refers to the radical -NR ⁷⁰ R ⁷¹ , wherein R ⁷⁰ and R ⁷¹ are each independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, and 5-10 membered heteroaryl. In some embodiments, amino refers to NH ₂ .

[0061] "Cyano" refers to the radical -CN.

[0062] "Hydroxy" or "hydroxyl" refers to the radical -OH.

[0063] In some embodiments, one or more nitrogen atoms of the disclosed compound, if present, are oxidized to the corresponding N -oxide.

[0064] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., a “substituted” or “unsubstituted” alkyl, a “substituted” or “unsubstituted” alkenyl, a “substituted” or “unsubstituted” alkynyl, a “substituted” or “unsubstituted” cycloalkyl, a “substituted” or “unsubstituted” heterocyclyl, a “substituted” or “unsubstituted” aryl, or a “substituted” or “unsubstituted” heteroaryl group). In general, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen present in the group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation, e.g., by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents on organic compounds, such as any of the substituents described herein, that result in the formation of a stable compound. The present disclosure contemplates any and all such combinations to produce a stable compound. For the purposes of this description, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein that satisfies the valence of the heteroatoms and results in the formation of a stable moiety.

[0065] Two or more substituents may optionally be joined to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. The so-called ring substituents are typically, although not necessarily, attached to the cyclic backbone structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the cyclic backbone structure. For example, two ring-forming substituents attached to adjacent members of the cyclic backbone structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the backbone structure. For example, two ring-forming substituents attached to a single member of the cyclic backbone structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the backbone structure.

[0066] A "counter ion" or "anionic counter ion" is a negatively charged group bonded to a cationic quaternary amino group to maintain electron neutrality. Examples of counterions include halide ions ( e.g. , F- ^{, Cl-} , Br- ^{, I-} ), _{NO3- ,} ^ClO4- , _OH- , ^{H2PO4- ,} HSO4-), sulfonate ions ₍ e.g. , methanesulfonate, trifluoromethanesulfonate ^, p-toluenesulfonate, ^{benzenesulfonate} , 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene- ₁ -sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions ( e.g. , acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0067] The term "pharmaceutically acceptable salts" includes salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be prepared by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include the sodium, potassium, calcium, ammonium, organic amino, or magnesium salt or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be prepared by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarboxylic, phosphoric, monohydrophosphoric, dihydrophosphoric, sulfuric, monohydrosulfuric, hydroiodic or phosphorous acids, etc., as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolyl sulfonic, citric, tartaric, methanesulfonic, etc. Also included are salts of amino acids such as arginate, etc., and salts of organic acids such as glucuronic or galactunic acids, etc. (See, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups which allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present disclosure. Salts tend to be more soluble in aqueous or other protic solvents which are the corresponding free base forms. In other cases, the formulation may be a lyophilized powder in a first buffer, for example, 1-50 mM histidine, 0.1-2% sucrose, 2-7% mannitol in the pH range of 4.5 to 5.5, which is combined with a second buffer prior to use.

[0068] Thus, the compounds of the present invention can exist in the form of salts, for example, with pharmaceutically acceptable acids. The present description includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0069] Neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0070] As used herein, the term "salt" refers to acidic or basic salts of the compounds used in the methods of the present disclosure. Illustrative examples of suitable salts are mineral acid salts (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (acetic acid, propionic acid, glutamic acid, citric acid, etc.), quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0071] Some compounds of the present disclosure contain asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)- or as (D)- or (L)- for amino acids, and individual isomers are included within the scope of the present disclosure. Compounds of the present invention do not include those known in the art to be too unstable to synthesize and/or isolate. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or separated using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise indicated, the compounds are intended to include the E and Z geometric isomers.

[0072] As used herein, the term "isomers" refers to compounds having the same number and kind of atoms and hence the same molecular weight, but differing in the structural arrangement or configuration of the atoms.

[0073] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and that are readily convertible from one isomeric form to the other.

[0074] It will be apparent to one skilled in the art that some of the compounds of this disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the disclosure.

[0075] The terms "treating" or "treating" include preventing or delaying the onset of symptoms, complications, or biochemical signs of a disease, alleviating or ameliorating symptoms, or stopping or inhibiting the further progression of a disease, condition, or disorder. The terms "treating" or "treatment" include any effect, such as reducing, reducing, modulating, or eliminating, that results in an improvement in a condition, disease, disorder, or the like. For example, the methods defined herein treat cancer by reducing or reducing or preventing the onset, growth, metastasis, or progression of cancer or by reducing a symptom of cancer. The term "treating" and combinations thereof include preventing an injury, pathology, condition, or disease (e.g., preventing the development of one or more symptoms of a disease, disorder, or condition described herein).

[0076] An "effective amount" is an amount sufficient to achieve the stated purpose (e.g., to achieve the effect for which it is administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, or to reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to help treat, prevent, or reduce a symptom or symptoms of a disease, which may also be referred to as a "therapeutically effective amount." A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will produce the intended prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or symptoms thereof. The full prophylactic effect need not occur with a single dose, but may only occur after a series of doses. Thus, a prophylactically effective amount may be administered in a single administration or multiple administrations. The exact amounts will depend on the purpose of treatment and can be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0077] “Reduce” a symptom or symptoms (and grammatical equivalents of this phrase) means to reduce the severity or frequency of the symptom(s) or to eliminate the symptom(s).

[0078] "Control" or "control experiment" is used in its simple, ordinary meaning and refers to an experiment in which the subjects or reactants of the experiment are treated as in a parallel experiment, except for the omission of a procedure, reagent, or experimental variable. In some cases, a control is used as a standard of comparison in assessing experimental effects.

[0079] "Contact" is used in its simple, ordinary meaning and refers to a process that allows at least two different species (e.g., chemical compounds, including biomolecules or cells) to become close enough to react, interact, or physically touch. However, it should be understood that the resulting reaction product may be obtained directly from the reaction between the added reactants or from an intermediate product of one or more added reactants that may be formed in the reaction mixture. The term "contacting" may include allowing two species to react, interact, or physically touch, where the two species may be a compound as described herein and a protein or enzyme, such as a protein tyrosine phosphatase, such as non-receptor protein tyrosine phosphatase type 2 (PTPN2) or non-receptor protein tyrosine phosphatase type 1 (PTPN1).

[0080] As defined herein, the term "inhibition," "inhibit," "inhibiting," and the like, when used in connection with a protein-inhibitor (e.g., antagonist) interaction, means a negative effect (e.g., a decrease) on the activity or function of a protein relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or disease symptoms. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction pathway or signaling pathway. Thus, inhibition includes at least partially, partially or completely blocking the stimulation of, reducing, preventing or delaying the activation of, or inactivating, desensitizing or suppressing signal transduction or enzymatic activity or the amount of a protein. In some embodiments, inhibiting refers to decreasing the activity of a protein tyrosine phosphatase, such as non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTPN1). Thus, inhibiting may include at least partially, partially or completely decreasing the stimulation, decreasing or decreasing the activation, or inactivating, desensitizing or suppressing the signal transduction or enzymatic activity or amount of a protein tyrosine phosphatase, such as non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTPN1).

[0081] A "patient" or "subject" in need thereof refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a compound or pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient is a human. In some embodiments, the patient is a domestic animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is a livestock. In some embodiments, the patient is a mammal. In some embodiments, the patient is a cat. In some embodiments, the patient is a horse. In some embodiments, the patient is cattle. In some embodiments, the patient is a canine. In some embodiments, the patient is a feline. In some embodiments, the patient is a primate. In some embodiments, the patient is a monkey. In some embodiments, the patient is a mouse. In some embodiments, the patient is an experimental animal. In some embodiments, the patient is a rat. In some embodiments, the patient is a hamster. In some embodiments, the patient is a test animal. In some embodiments, the patient is a neonatal animal. In some embodiments, the patient is a neonatal human. In some embodiments, the patient is a neonatal mammal. In some embodiments, the patient is an elderly animal. In some embodiments, the patient is an elderly human. In some embodiments, the patient is an elderly mammal. In some embodiments, the patient is a geriatric patient.

[0082] "Disease," "disorder," or "condition" refers to a condition or health state of a patient or subject that is treatable with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein comprise reducing or eliminating one or more symptoms of the disease, disorder, or condition, such as by administering a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0083] The term "signaling pathway" as used herein refers to a series of interactions between cellular and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which in turn may transmit a change in additional components that is not necessarily propagated to other components of the signaling pathway.

[0084] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that facilitates the administration of the active agent and absorption by a subject, and can be included in the compositions according to the present disclosure without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, saline solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine and colorants and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffers, colorants and/or flavoring substances and the like, which do not enter into negative reactions with the compounds of the description. A person skilled in the art will understand that other pharmaceutical excipients can be used in the present description.

[0085] The term "preparation" is intended to include a formulation of the active compound with an encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier which is thus associated with it. Capsules and lozenges are similarly included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0086] As used herein, the term "administration" means oral administration, administration by suppository, by topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or by implantation of a slow-release device, such as a mini-osmotic pump, into a subject. Administration may be by any route, including parenteral and transdermal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administration" is meant that the compound or composition described herein is administered simultaneously, just before or immediately after the administration of one or more additional therapeutic agents (e.g., an anti-cancer agent, a chemotherapeutic agent, or an immunotherapeutic agent). The compounds or compositions described herein can be administered separately or they can be administered simultaneously to a patient. By co-administration is meant the simultaneous or sequential administration of a compound or composition alone or in combination (more than one compound or agent). Thus, if desired, the drugs can be combined with other active substances (e.g., to reduce metabolic degradation).

[0087] 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),

Connections

[0088] This document, for example, discloses a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Z is selected from the group consisting of C(H)(R ³ ), bond and N(R ⁸ );

R ¹ is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -OC _1-6 alkyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -OC _1-6 alkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ;

R ² is selected from the group consisting of hydrogen, -C _1-6 alkyl, -C _2-6 alkenyl, -OC _1-6 alkyl, -NH ₂ , -N(R ^a )-C _1-8 alkyl, -N(R ^a )-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ , -C _{1-6 alkylene} -N(R ^a )-C _1-6 alkyl, -C _1-6 alkylene-N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkylene-N(R ^a )(R ^b ), _-N (R ^a )-(C=N(R ^b ))-C _1-6 alkyl, -S(O) _w -C _1-6 alkyl, -C(O)-N(R ^a )-C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^a )-C _1-6 alkyl, -OC(O)-N(R ^a )-phenyl, -N(R ^a )-C(O)-OC _1-6 alkyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -N(R ^a )-4-6-membered heterocyclyl, -C _1-6 alkylene-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^a )-C _1-6 alkylene-phenyl;

where -C _1-6 alkyl, -C _2-6 alkenyl, -OC _1-6 alkyl, -N(R ^a )-C _1-8 alkyl, -N(R ^a )-C _3-6 cycloalkyl, -N (R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ , -C ₁ - ₆ alkylene-N(R ^a )-C _1-6 alkyl, -C ₁ - ₆ alkylene-N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-(C=N(R ^b ))-C _1-6 alkyl, -S(O) _w -C _1-6 alkyl, -C(O)-N(R ^a )-C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^a )-C _1-6 alkyl, -OC(O)-N(R ^a )-phenyl, -N(R ^a )-C(O)-OC _1-6 alkyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene-4-6 membered heterocyclyl, -OC _1-6 alkylene-4-6 membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4-6 membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^a )-C _1-6 alkylene-phenyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents, each independently selected from R ^g ;

wherein if the 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, -N(R ^a )-4- to 6-membered heterocyclyl, -C _1-6 alkylene-4- to 6-membered heterocyclyl, -OC _1-6 alkylene-4- to 6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4- to 6-membered heterocyclyl or -N(R ^a )-C _1-6 alkylene-5- to 6-membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with R ^h ; and

where if Z is C(H)(R ³ ), then R ² is not -CH ₂ -CH ₃ ; R ^2' is selected from the group consisting of hydrogen, -NR ^a R ^b and -N(R ^a )-N(R ^b )-C(O)-phenyl;

R ³ is selected from the group consisting of hydrogen, -C _1-6 alkyl, -OC _1-6 alkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkyl, -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, _-S (O) _w -C _1-6 alkyl, -C(O)-N(R ^a )-C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein _-C1-6 alkyl, _-OC1-6 alkyl, _{-OC1-6 alkylene} - _C3-6 cycloalkyl, -N(R ^a ) _-C1-6 alkyl, -N(R ^a ) _-C1-6 alkylene- _C3-6 cycloalkyl, -S(O) _w - _C1-6 alkyl, -C(O)-N(R ^a ) _-C1-6 alkyl, -N(R ^a )-C(O) _-C1-6 alkyl and _-C1-6 alkylene-4-6-membered heterocyclyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁴ is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁵ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁶ is selected from the group consisting of hydrogen and deuterium;

R ⁷ is selected from the group consisting of hydrogen and deuterium;

R ⁸ is selected from the group consisting of hydrogen and C _1-6 alkyl,

R ^g is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, R ^a R ^b N-, R ^a R ^b NC(O)-, R ^a R ^b N-SO _w -, R ^a R ^b NC(O)-N(R ^a )-, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkylene-, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^a )-, C _1-6 alkyl-N(R ^a )-C(O)-, C _1-6 alkyl-C(O)-N(R ^a ), C _1-6 alkyl-N(R ^a )-C(O)-N(R ^a )-, C _1-6 alkyl-N(R ^a )-SO _w -, C _3-6 cycloalkyl-N(R ^a )-SO _w -, C _1-6 alkyl-SO _w -N(R ^a )-, C _3-6 cycloalkyl-SO _w -N(R ^a )-, C _1-6 alkoxy-C(O)-N(R ^a )-, C _1-6 alkyl-C(O)-N(R ^a )-C _1-6 alkyl-, C _1-6 alkyl-N(R ^a )-C(O)-C _1-6 alkyl- and C _1-6 alkoxy-C _1-6 alkyl-; where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^a )-, C _1-6 alkyl-N(R ^a )-C(O)-, C _1-6 alkyl-C(O)-N(R ^a ), C _1-6 alkyl-N(R ^a )-C(O)-N(R ^a )-, _C1-6 alkyl-N(R ^a )-SO _w -, _C3-6 cycloalkyl-N(R ^a )-SO _w -, _C1-6 alkyl-SO _w -N(R ^a )-, _C3-6 cycloalkyl-SO _w -N(R ^a )-, _C1-6 alkoxy-C(O)-N(R ^a )-, _C1-6 alkyl-C(O)-N(R ^a ) _-C1-6 alkyl-, _C1-6 alkyl-N(R ^a )-C(O) _-C1-6 alkyl- and _C1-6 alkoxy- _C1-6 alkyl- may be optionally substituted with one, two, three or more substituents each independently selected from R ^P ;

R ^h is independently selected for each occurrence from the group consisting of C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)-, and R ^a R ^b N-SO ₂ -; wherein C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)- and R ^a R ^b N-SO ₂ - may optionally be substituted with one, two, three or more substituents, each of which is independently selected from R ^P ;

R ^P is independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, R ^a R ^b N-, R ^a R ^b N-carbonyl-, R ^a R ^b N-SO ₂ -, and R ^a R ^b N-carbonyl-N(R ^a )-;

R ^a and R ^b are independently selected for each occurrence from the group consisting of hydrogen and C _1-6 alkyl; wherein C _1-6 alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

or R ^a and R ^b together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

R ^c is independently selected for each occurrence from the group consisting of hydroxyl, C _1-4 alkyl, and phenyl; and

w is 0, 1, or 2.

[0089] For example, a compound disclosed herein may be represented by Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -OC _1-6 alkyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -OC _1-6 alkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ;

R ² is selected from the group consisting of hydrogen, -C _1-6 alkyl, -C _2-6 alkenyl, -OC _1-6 alkyl, -NH ₂ , -N(R ^a )-C _1-8 alkyl, -N(R ^a )-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ , -N(R ^a )-(C=N(R ^b ))-C _1-6 alkyl, -S(O) _w -C _1-6 alkyl, -C(O)-N(R ^a )-C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^a )-C _1-6 alkyl, -OC(O)-N(R ^a )-phenyl, -N(R ^a )-C(O)-OC _1-6 alkyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene-4-6 membered heterocyclyl, -OC _1-6 alkylene-4-6 membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4-6 membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-5-6 membered heteroaryl and -N(R ^a )-C _1-6 alkylene phenyl;

where -C _1-6 alkyl, -C _2-6 alkenyl, -OC _1-6 alkyl, -N(R ^a )-C _1-8 alkyl, -N(R ^a )-C _3-6 cycloalkyl, -N (R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ , -N(R ^a )-(C=N(R ^b ))-C _1-6 alkyl, -S(O) _w -C _1-6 alkyl, -C(O)-N(R ^a )- C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^a )-C _1-6 alkyl, -OC(O)-N( R ^a )-phenyl, -N(R ^a )-C(O)-OC _1-6 alkyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -N(R ^a )-4-6-membered heterocyclyl, -C _1-6 alkylene-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl , -N(R ^a )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^a )-C _{1 -6} alkylene-phenyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents, each independently selected from R ^g ; and

wherein if the 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, -N(R ^a )-4- to 6-membered heterocyclyl, -C _1-6 alkylene-4- to 6-membered heterocyclyl, -OC _1-6 alkylene-4- to 6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4- to 6-membered heterocyclyl or -N(R ^a )-C _1-6 alkylene-5- to 6-membered heteroaryl contains a substitutable ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

R ^2' is selected from the group consisting of hydrogen, -NR ^a R ^b and -N(R ^a )-N(R ^b )-C(O)-phenyl;

R ³ is selected from the group consisting of hydrogen, -C _1-6 alkyl, -OC _1-6 alkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkyl, -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, _-S (O) _w -C _1-6 alkyl, -C(O)-N(R ^a )-C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein -C _1-6 alkyl, -OC _1-6 alkyl, -OC _1-6 alkylene _- C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkyl, -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -S(O) _w -C _1-6 alkyl, -C(O)-N(R ^a )-C _1-6 alkyl, -N(R ^a )-C(O)-C _1-6 alkyl and -C _1-6 alkylene-4-6-membered heterocyclyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁴ is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁵ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein C _1-6 alkyl, C _3-6 cycloalkyl and -C _1-6 alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if the -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h ;

R ⁶ is selected from the group consisting of hydrogen and deuterium;

R ⁷ is selected from the group consisting of hydrogen and deuterium;

R ^g is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, R ^a R ^b N-, R ^a R ^b NC(O)-, R ^a R ^b N-SO _w -, R ^a R ^b NC(O)-N(R ^a )-, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkylene-, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^a )-, C _1-6 alkyl-N(R ^a )-C(O)-, C _1-6 alkyl-C(O)-N(R ^a ), C _1-6 alkyl-N(R ^a )-C(O)-N(R ^a )-, C _1-6 alkyl-N(R ^a )-SO _w -, C _3-6 cycloalkyl-N(R ^a )-SO _w -, C _1-6 alkyl-SO _w -N(R ^a )-, C _3-6 cycloalkyl-SO _w -N(R ^a )-, C _1-6 alkoxy-C(O)-N(R ^a )-, C _1-6 alkyl-C(O)-N(R ^a )-C _1-6 alkyl-, C _1-6 alkyl-N(R ^a )-C(O)-C _1-6 alkyl- and C _1-6 alkoxy-C _1-6 alkyl-; where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^a )-, C _1-6 alkyl-N(R ^a )-C(O)-, C _1-6 alkyl-C(O)-N(R ^a ), C _1-6 alkyl-N(R ^a )-C(O)-N(R ^a )-, _C1-6 alkyl-N(R ^a )-SO _w -, _C3-6 cycloalkyl-N(R ^a )-SO _w -, _C1-6 alkyl-SO _w -N(R ^a )-, _C3-6 cycloalkyl-SO _w -N(R ^a )-, _C1-6 alkoxy-C(O)-N(R ^a )-, _C1-6 alkyl-C(O)-N(R ^a ) _-C1-6 alkyl-, _C1-6 alkyl-N(R ^a )-C(O) _-C1-6 alkyl- and _C1-6 alkoxy- _C1-6 alkyl- may be optionally substituted with one, two, three or more substituents each independently selected from R ^P ;

R ^h is independently selected for each occurrence from the group consisting of C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)-, and R ^a R ^b N-SO ₂ -; wherein C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)- and R ^a R ^b N-SO ₂ - may optionally be substituted with one, two, three or more substituents, each of which is independently selected from R ^P ;

R ^P is independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, R ^a R ^b N-, R ^a R ^b N-carbonyl-, R ^a R ^b N-SO ₂ -, and R ^a R ^b N-carbonyl-N(R ^a )-;

R ^a and R ^b are independently selected for each occurrence from the group consisting of hydrogen and C _1-6 alkyl; wherein C _1-6 alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

or R ^a and R ^b together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

R ^c is independently selected for each occurrence from the group consisting of hydroxyl, C _1-4 alkyl, and phenyl; and

w is 0, 1, or 2.

[0090] In some embodiments, R ¹ is selected from the group consisting of hydrogen and fluorine. In some embodiments, R ¹ is hydrogen.

[0091] In some embodiments, R ² is -OC _1-6 alkyl; wherein R ² may be optionally substituted with one, two, three, or more substituents, each independently selected from R ^g . In some embodiments, R ² may be optionally substituted with one, two, three, or more substituents, each independently selected for each occurrence from the group consisting of fluoro, hydroxyl, C _1-6 alkoxy, and R ^a R ^b N-. For example, R ² may be selected from the group consisting of: -OCH ₃ , , , And .

[0092] In other embodiments, R ² is -N(R ^a )-C _1-8 alkyl, wherein R ² may be optionally substituted with one, two, three, or more substituents each independently selected from R ^g . In some embodiments, R ² may be optionally substituted with one, two, three, or more substituents each independently selected from the group consisting of fluoro, hydroxyl, cyano, and C _1-6 alkoxy, wherein the C _1-6 alkoxy may be optionally substituted with one, two, or three fluoro. In some embodiments, R ^a is hydrogen. In some embodiments, R ² is -N(R ^a )-C ₅ alkyl. For example, R ² may be selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , And .

[0093] In some embodiments, R ² is selected from the group consisting of -NH ₂ , -N(R ^a )-C _1-8 alkyl, -N(R ^a )-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ , -N(R ^a )-4- to 6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4- to 6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-5- to 6-membered heteroaryl, and -N(R ^a )-C _1-6 alkylene-phenyl, and this moiety is attached to the tetralin bicycle to form the R enantiomer;

wherein -N(R ^a )-C _1-8 alkyl, -N(R ^a )-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ , -N(R ^a )-4-6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^a )-C _1-6 alkylene-phenyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and

wherein if -N(R ^a )-4-6-membered heterocyclyl, -N(R ^a )-C _1-6 alkylene-4-6-membered heterocyclyl or -N(R ^a )-C _1-6 alkylene-5-6-membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^h .

[0094] For example, R ² may be selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , And .

[0095] In some embodiments, R ² is . In other embodiments, R ² is .

[0096] In some embodiments, R ² is -C _1-6 alkylene-C _3-6 cycloalkyl. For example, R ² can be represented by .

[0097] In other embodiments, R ² is -OC _1-6 alkylene-C _3-6 cycloalkyl, wherein R ² may be optionally substituted with one, two, three, or more substituents each independently selected from R ^g . In some embodiments, R ² may be optionally substituted with one, two, or three fluorine atoms. For example, R ² may be selected from the group consisting of And .

[0098] In further embodiments, R ² is -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, wherein R ² may be optionally substituted with one, two, three or more substituents each independently selected from R ^g . For example, R ² may be selected from the group consisting of , , , , , , , And .

[0099] For example, R ² may be selected from the group consisting of , , , , , , , And .

[00100] In still further embodiments, R ² is -N(R ^a )-C _1-6 alkylene-4-6-membered heterocyclyl. For example, R ² can be .

[00101] For example, R ² can be represented as .

[00102] In some embodiments, R ² is -N(R ^a )-C _1-6 alkylenephenyl, wherein R ² may be optionally substituted with one, two, three, or more substituents each independently selected from R ^g . In some embodiments, R ² may be optionally substituted with one, two, or three fluorine atoms. For example, R ² may be .

[00103] For example, R ² can be represented as .

[00104] In some embodiments, R ² is -N(R ^a )-C _1-6 alkylene-5-6-membered heteroaryl, wherein R ² may be optionally substituted with one, two, three, or more substituents each independently selected from R ^g . For example, R ² may be selected from the group consisting of , , , , , And .

[00105] For example, R ² may be selected from the group consisting of , , , , , And .

[00106] In other embodiments, R ² is a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with one, two, three or more substituents each independently selected from R ^g , and wherein if the 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom may be optionally substituted with R ^h . For example, R ² can be pyrrolidinyl, wherein the pyrrolidinyl may be optionally substituted with R ^h . In some embodiments, R ^h is selected from the group consisting of C _1-6 alkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, and C _3-6 cycloalkyl-S(O) ₂ -. For example, R ² can be selected from the group consisting of , , , And .

[00107] In further embodiments, R ² is -OC(O)-N(R ^a )-phenyl. For example, R ² can be represented by .

[00108] In some embodiments, R ² is -N(R ^a )-C _1-6 alkylene-Si(R ^c ) ₃ . For example, R ² can be selected from the group consisting of And .

[00109] For example, R ² may be selected from the group consisting of And ..

[00110]

[00111] In some embodiments, R ² is -N(R ^a )-(C=N(R ^b ))-C _1-6 alkyl. For example, R ² can be .

[00112] In some embodiments, R ² is -N(R ^a )-C _3-6 cycloalkyl, wherein R ² may be optionally substituted with one, two, three, or more substituents each independently selected from R ^g . For example, R ² may be . For example, R ² can be represented as .

[00113] In some embodiments, R ² is hydrogen. In other embodiments, R ^2' is selected from the group consisting of hydrogen and -NH ₂ .

[00114] In some embodiments, R ³ is hydrogen. In other embodiments, R ³ is selected from the group consisting of -OC _1-6 alkyl and -OC _1-6 alkylene-C _3-6 cycloalkyl, wherein R ³ may be optionally substituted with one, two, three, or more substituents each independently selected from R ^g . For example, R ³ can be selected from the group consisting of -OCH ₃ , , , , , And .

[00115] In some embodiments, R ³ is selected from the group consisting of -N(R ^a )-C _1-6 alkyl and -N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, wherein R ³ may be optionally substituted with one, two, _three or more substituents each independently selected from R ^g . For example, R ³ may be selected from the group consisting of , , And .

[00116] Also disclosed herein is a compound represented by Formula I(c):

.

[00117] In some embodiments, R ² is selected from the group consisting of _{-C 1-6} alkylene-N( _R ^a )-C _1-6 alkyl, -C _1-6 alkylene-N(R ^a )(R ^b ), and -C _1-6 alkylene-N(R ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, wherein R ² may be optionally substituted with one, two, three, or more substituents each independently selected from R ^g . For example, R ² may be selected from the group consisting of

, , , , And .

[00118] Also disclosed herein is a compound represented by Formula I(d):

.

[00119] In some embodiments, R ² is C _1-6 alkyl.

[00120] In other embodiments, R ⁴ is hydrogen. In further embodiments, R ⁵ is selected from the group consisting of hydrogen and fluoro. In some embodiments, R ⁶ is hydrogen. In still further embodiments, R ⁷ is hydrogen.

[00121] This document also discloses a compound represented by Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

X ^II1 is selected from the group consisting of O and C(R ^II1 )(R ^II1' );

X ^II4 is selected from the group consisting of O and C(R ^II4 )(R ^II4' );

where at least one of X ^II1 and X ^II4 is O;

R ^II1 and R ^II1' are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _3-6 cycloalkyl;

wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ;

R ^II2 is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, -N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -S(O) ₂ -C _1-6 alkyl, -C(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)-OC _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C _1-6 alkylene-4-6 membered heterocyclyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^IIa )-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^IIa )-C _1-6 alkylene-phenyl;

where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, -N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -S(O) ₂ -C _1-6 alkyl, -C(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)- OC _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C _1-6 alkylene-4-6-membered heterocyclyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -N (R ^IIa )-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-5-6-membered heteroaryl and -N(R ^IIa )-C _1-6 alkylene-phenyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents, each of which is independently selected from R ^IIg ;

where, if 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-4-6 membered heterocyclyl, or -N(R ^IIa )-C _1-6 alkylene-5-6 membered heteroaryl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^IIh ; And

where if R ^II2 is -OC _1-6 alkyl, -N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -S(O ) ₂ -C _1-6 alkyl, -N(R ^IIa )-C(O)-C _1-6 alkyl, -OC(O)-N(R ^IIa )-C _1-6 alkyl, -N(R ^IIa )-C(O)-OC _1-6 alkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -N(R ^IIa )-4-6-membered heterocyclyl, -OC _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-4-6-membered heterocyclyl, -N(R ^IIa )-C _1-6 alkylene-5-6-membered heteroaryl or -N(R ^IIa )-C _1-6 alkylene-phenyl; then X ^II1 is C(R ^II1 )(R ^II1' ) and X ^II4 is O;

R ^II2' is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-5-6-membered heteroaryl and -C _1-6 alkylene-4-6-membered heterocyclyl;

wherein _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, phenyl, 5-6-membered heteroaryl, 4-6-membered heterocyclyl, _-C1-6 alkylene- _C3-6 cycloalkyl, _-C1-6 alkylene-phenyl, _-C1-6 alkylene-5-6-membered heteroaryl and _-C1-6 alkylene-4-6-membered heterocyclyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ; and

wherein if the 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -C _1-6 alkylene-5-6 membered heteroaryl or -C _1-6 alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^IIh ;

R ^II3 and R ^II3' are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _3-6 cycloalkyl;

wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ;

R ^II4 and R ^II4' are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _3-6 cycloalkyl;

wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ;

R ^II5 is selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl and C _3-6 cycloalkyl;

wherein C _1-6 alkyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIg ;

R ^II6 is selected from the group consisting of hydrogen and deuterium;

R ^II7 is selected from the group consisting of hydrogen and deuterium;

R ^IIg is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, R ^IIa R ^IIb N-, R ^IIa R ^IIb NC(O)-, R ^{IIa IIb} N-SO _w -, R ^IIa R ^IIb NC(O)-N(R ^IIIa )-, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkylene-, C _1-6 alkoxy, C _3-6 alkenyloxy, C _{3-6 alkynyloxy, C 3-6 cycloalkoxy} , C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^IIa )-, C _1-6 alkyl-N(R ^IIa )-C(O)-, C _1-6 alkyl-C(O)-N(R ^IIa ), C _1-6 alkyl-N(R ^IIa )-C(O)-N(R ^IIa )-, C _1-6 alkyl-N(R ^IIa )-SO _w -, C _3-6 cycloalkyl-N(R ^IIa )-SO _w -, C _1-6 alkyl-SO _w -N(R ^IIa )-, C _3-6 cycloalkyl-SO _w -N(R ^IIa )-, C _1-6 alkoxy-C(O)-N(R ^IIa )-, C _1-6 alkyl-C(O)-N(R ^IIa )-C _1-6 alkyl-, C _1-6 alkyl-N(R ^IIa )-C(O)-C _1-6 alkyl- and C _1-6 alkoxy-C _1-6 alkyl-; where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^IIa )-, C _1-6 alkyl-N(R ^IIa )-C(O)-, C _1-6 alkyl-C(O)-N(R ^IIa ), C _1-6 alkyl-N(R ^IIa) )-C(O)-N(R ^IIa )-, _C1-6 alkyl-N(R ^IIa ) _-SOw- , _C3-6 cycloalkyl-N(R ^IIa )-SOw-, _C1-6 alkyl-SOw _- N(R ^IIa )-, _C3-6 cycloalkyl-SOw _- N( _R ^IIa )-, _C1-6 alkoxy-C(O)-N(R ^IIa )-, _C1-6 alkyl-C(O)-N(R ^IIa ) _-C1-6 alkyl-, _C1-6 alkyl-N(R ^IIa )-C(O) _-C1-6 alkyl- and _C1-6 alkoxy- _C1-6 alkyl- may be optionally substituted with one, two, three or more substituents each independently selected from R ^IIP ;

R ^IIh is independently selected for each occurrence from the group consisting of C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^IIa R ^IIb NC(O)-, and R ^IIa R ^IIb N-SO ₂ -; wherein C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^IIa R ^IIb NC(O)- and R ^IIa R ^IIb N-SO ₂ - may be optionally substituted with one, two, three or more substituents, each of which is independently selected from R ^IIP ;

R ^IIP is independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, R ^IIa R ^IIb N-, R ^IIa R ^IIb N-carbonyl-, R ^IIa R ^IIb N-SO ₂ -, and R ^IIa R ^IIb N-carbonyl-N(R ^IIa )-;

R ^IIa and R ^IIb are independently selected for each occurrence from the group consisting of hydrogen and C _1-3 alkyl; wherein C _1-3 alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

or R ^IIa and R ^IIb together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and

w is 0, 1, or 2.

[00122] In some embodiments, each of R ^II5 , R ^II6 , and R ^II7 is hydrogen. In other embodiments, either R ^II1 and R ^II1' or R ^II4 and R ^II4' are each hydrogen.

[00123] In some embodiments, the compound disclosed herein is

or .

[00124] For example, each of R ^II2 and R ^II2' can be independently selected from the group consisting of hydrogen and -CH ₃ . For example, each of R ^II3 and R ^II3' can be independently selected from the group consisting of hydrogen and -CH ₃ .

[00125] This document also discloses a compound represented by Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R ^III1 is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^III2 is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl, 4-7-membered heterocyclyl, 5-6-membered heteroaryl, -C _1-6 alkylene-C _3-8 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-4-7-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C(O)-C _1-6 alkyl, _-C ⁽ O)-OC _1-6 alkyl, -C(O)-C _1-6 alkylene-C _3-8 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-phenyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-4-7-membered heterocyclyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-5-6-membered heteroaryl, -C=N(R ^IIIa )-C _1-6 alkyl and -S(O) ₂ -C _1-6 alkyl;

where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl, 4-7-membered heterocyclyl, 5-6-membered heteroaryl, -C _1-6 alkylene-C _3-8 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-4-7-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C(O)-C _1-6 alkyl, -C(O)-OC _1-6 alkyl, -C(O)-C _1-6 alkylene-C _3-8 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-phenyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-4-7-membered heterocyclyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-5-6-membered heteroaryl, -C=N(R ^IIIa )-C _1-6 alkyl and -S(O) ₂ -C _1-6 alkyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIIg ; and

where, if 4-7-membered heterocyclyl, 5-6-membered heteroaryl, -C _1-6 alkylene-4-7-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, -C(O) -N(R ^IIIa )-C _1-6 alkylene-4-7-membered heterocyclyl or -C(O)-N(R ^IIIa )-C _1-6 alkylene 5-6 membered heteroaryl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^IIIh ;

R ^III3 is selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^III4 is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^III4' is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R ^III5 is selected from the group consisting of hydrogen, halogen and C _1-6 alkyl;

R ^III6 is selected from the group consisting of hydrogen and deuterium;

R ^III7 is selected from the group consisting of hydrogen and deuterium;

R ^IIIg is independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, R ^IIIa R ^IIIb N-, R ^IIIa R ^IIIb NC(O)-, R ^{IIIa IIIb} N-SO _w -, R ^IIIa R ^IIIb NC(O)-N(R ^IIIa )-, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkylene-, C _1-6 alkoxy, C _3-6 alkenyloxy, C _{3-6 alkynyloxy, C 3-6 cycloalkoxy} , C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^IIIa )-, C _1-6 alkyl-N(R ^IIIa )-C(O)-, C _1-6 alkyl-C(O)-N(R ^IIIa ), C _1-6 alkyl-N(R ^IIIa )-C(O)-N(R ^IIIa )-, C _1-6 alkyl-N(R ^IIIa )-SO _w -, C _3-6 cycloalkyl-N(R ^IIIa )-SO _w -, C _1-6 alkyl-SO _w -N(R ^IIIa )-, C _3-6 cycloalkyl-SO _w -N(R ^IIIa )-, C _1-6 alkoxy-C(O)-N(R ^IIIa )-, C _1-6 alkyl-C(O)-N(R ^IIIa )-C _1-6 alkyl-, C _1-6 alkyl-N(R ^IIIa )-C(O)-C _1-6 alkyl-, C _1-6 alkoxy-C _1-6 alkyl- and 5-6-membered heteroaryl; where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkoxy, C _3-6 alkenyloxy, C _3-6 alkynyloxy, C _3-6 cycloalkoxy, C _1-6 alkyl-C(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-C(O)-O-, C _1-6 alkyl-S(O) _w -, C _1-6 alkyl-N(R ^IIIa )-, C _1-6 alkyl-N(R ^IIIa )-C(O)-, C _1-6 alkyl-C(O)-N(R ^IIIa ), C _1-6 alkyl-N(R ^IIIa) )-C(O)-N(R ^IIIa )-, _C1-6 alkyl-N(R ^IIIa ) _-SOw- , _C3-6 cycloalkyl-N(R ^IIIa )-SOw-, _C1-6 alkyl-SOw _- N(R ^IIIa )-, _C3-6 cycloalkyl-SOw _- N( _R ^IIIa )-, _C1-6 alkoxy-C(O)-N(R ^IIIa )-, _C1-6 alkyl-C(O)-N(R ^IIIa ) _-C1-6 alkyl-, _C1-6 alkyl-N(R ^IIIa )-C(O) _-C1-6 alkyl-, _C1-6 alkoxy- _C1-6 alkyl- and 5-6-membered heteroaryl may be optionally substituted with one, two, three or more substituents each independently selected from R ^IIIP ;

R ^IIIh is independently selected for each occurrence from the group consisting of C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^IIIa R ^IIIb NC(O)-, R ^IIIa R ^IIIb N-SO ₂ - and -C _1-6 alkylene-5-6-membered heteroaryl; wherein C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^IIIa R ^IIIb NC(O)-, R ^IIIa R ^IIIb N-SO ₂ - and -C _1-6 alkylene-5-6-membered heteroaryl may be optionally substituted with one, two, three or more substituents each independently selected from R ^IIIP ;

R ^IIIP for each occurrence is independently selected from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, R ^IIIa R ^IIIb N-, R ^IIIa R ^IIIb N-carbonyl-, R ^IIIa R ^IIIb N-SO ₂ - and R ^IIIa R ^IIIb N-carbonyl-N(R ^IIIa )-;

R ^IIIa and R ^IIIb are independently selected for each occurrence from the group consisting of hydrogen and C _1-3 alkyl; wherein C _1-3 alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl;

or R ^IIIa and R ^IIIb together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the 4-6 membered heterocyclyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and

w is 0, 1, or 2.

[00126] In some embodiments, R ^III5 is selected from the group consisting of hydrogen and fluoro. In other embodiments, R ^III6 and R ^III7 are each hydrogen. In further embodiments, R ^III4 and R ^III4' are each independently selected from the group consisting of hydrogen and fluoro. In yet further embodiments, R ^III1 , R ^III3 , R ^III4 and R ^III4' are each hydrogen.

[00127] For example, the compound disclosed herein is represented by:

.

[00128] In some embodiments, R ^III2 is selected from the group consisting of hydrogen, C _1-6 alkyl, and -C(O)-C _1-6 alkyl, wherein R ^III2 may be optionally substituted with one, two, three, or more substituents each independently selected from R ^IIIg . For example, R ^III2 may be selected from the group consisting of hydrogen, , , , , , , , , , , , , , , , And .

[00129] In other embodiments, R ^III2 is a 4-7 membered heterocyclyl, wherein the 4-7 membered heterocyclyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIIg ; and wherein if the 4-7 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with R ^IIIh . For example, R ^III2 may be selected from the group consisting of

, , , And .

[00130] In some embodiments, R ^III2 is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIIg ; and wherein if the 4-7 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with R ^IIIh . For example, R ^III2 may be represented by .

[00131] In some embodiments, R ^III2 is -C _1-6 alkylene-5 to 6-membered heteroaryl, wherein the -C _1-6 alkylene-5 to 6-membered heteroaryl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIIg ; and wherein if the 4 to 7-membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with R ^IIIh . For example, R ^III2 may be selected from the group consisting of

, , , , , , , , , , , , , , , , , , And .

[00132] In other embodiments, R ^III2 is -C _1-6 alkylenephenyl, wherein R ^III2 may be optionally substituted with one, two, three, or more substituents each independently selected from R ^IIIg . For example, R ^III2 may be selected from the group consisting of , , . And .

[00133] In further embodiments, R ^III2 is -C _1-6 alkylene-4-7-membered heterocyclyl, wherein the -C _1-6 alkylene-4-7-membered heterocyclyl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^IIIg ; and wherein if the -C _1-6 alkylene-4-7-membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may be optionally substituted with R ^IIIh . For example, R ^III2 can be selected from the group consisting of

, , , , , , , , , , , , And .

[00134] In some embodiments, R ^III2 is -C(O)-OC _1-6 alkyl, wherein R ^III2 may be optionally substituted with one, two, three, or more substituents each independently selected from R ^IIIg . For example, R ^III2 is selected from the group consisting of And .

[00135] In other embodiments, R ^III2 is -C(O)-N(R ^IIIa )-C _1-6 alkyl, wherein R ^III2 may be optionally substituted with one, two, three, or more substituents each independently selected from R ^IIIg . For example, R ^III2 may be selected from the group consisting of

, , , , , , And .

[00136] In further embodiments, R ^III2 is -C _1-6 alkylene-C _3-8 cycloalkyl, wherein R ^III2 may be optionally substituted with one, two, three or more substituents each independently selected from R ^IIIg . For example, R ^III2 may be selected from the group consisting of , , , , , , , , , , , , , And .

[00137] In some embodiments, R ^III2 is -C(O)-C _1-6 alkylene-C _3-8 cycloalkyl, wherein R ^III2 may be optionally substituted with one, two, three, or more substituents each independently selected from R ^IIIg . For example, R ^III2 may be .

[00138] In some embodiments, R ^III2 is -C=N(R ^IIIa )-C _1-6 alkyl. For example, R ^III2 can be represented by .

[00139] In other embodiments, R ^III2 is selected from the group consisting of -C(O)-N(R ^IIIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-phenyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-4-7-membered heterocyclyl, and -C(O)-N(R ^IIIa )-C _1-6 alkylene-5-6-membered heteroaryl, wherein -C(O)-N(R ^IIIa )-C _1-6 alkylene-C _3-6 cycloalkyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-phenyl, -C(O)-N(R ^IIIa )-C _1-6 alkylene-4-7-membered heterocyclyl, or -C(O)-N(R ^IIIa ) _{-C1-6alkylene} -5-6-membered heteroaryl may be optionally substituted on one or more available carbon atoms with one, two, three or more substituents each independently selected from m R ^IIIg ; and wherein if -C(O)-N(R ^IIIa ) _{-C1-6alkylene} -4-7-membered heterocyclyl or -C(O)-N(R ^IIIa ) _{-C1-6alkylene} -5-6-membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with R ^IIIh . For example, R ^III2 may be selected from the group consisting of , , , , , , , , , , And .

[00140] The present document further discloses a compound selected from the group consisting of:

5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin-1,1,3- trion;

5-[(7 R )-1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(7 S )-1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(5-fluoro-7-hydroxy-3,4-dihydro-2 H -1-benzopyran-6-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(5-fluoro-7-hydroxy-2,2-dimethyl-3,4-dihydro-2 H -1-benzopyran-6-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2,2-dimethyl-3,4-dihydro-2 H -1-benzopyran-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1,4-difluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalene-2-yl)-1λ ^6,2,5 -thiadiazolidine-1,1,3-trione;

5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 S )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin-1, 1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4-methoxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5- thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3-methoxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2,2-difluoro-2-phenylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(3-cyclopropyl-2,2-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ⁶ 2,5-thiadiazolidine -1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[methyl(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin-1,1 ,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4-methylpentyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[4,4,4-trifluoro-3-(trifluoromethyl)butyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 S )-7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[2-(pyridin-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 RS )-1-fluoro-3-hydroxy-7-[(3 RS )-pyrrolidin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 RS )-7-[(3 RS )-1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 RS )-1-fluoro-3-hydroxy-7-[(3 SR )-pyrrolidin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 RS )-7-[(3 SR )-1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[2-(1 H -pyrazol-1-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(4-methylpentanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(4-methylpentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 S )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(7 R )-1-fluoro-3-hydroxy-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl phenylcarbamate;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ^6,2,5 -thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene-2-yl ]amino}-2,2-dimethylbutanenitrile;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3-hydroxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3-methoxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(5,5,5-trifluoropentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ^6,2,5 -thiadiazolidin-1,1 ,3-trione;

5-(1-fluoro-3-hydroxy-7-{(3-methylbutyl)[(pyridin-2-yl)methyl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl)-1λ ⁶ , 2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[(pyridin-2-yl)methyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-2-hydroxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(7-{[2-(difluoromethoxy)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-pentanimidoyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(3-cyclopropylpropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(2-azaspiro[3.3]heptan-6-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ^6,2,5 -thiadiazolidine -1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(6,6,6-trifluorohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(3,3-difluorocyclobutyl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(azetidin-3-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[(propan-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(azetidin-3-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(azetidin-3-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{(3-methylbutyl)[2-(pyridin-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[(spiro[2.3]hexan-5-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[2-(trifluoromethoxy)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3-hydroxy-3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

3-hydroxybutyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate;

5-{1-fluoro-3-hydroxy-7-[3-(propan-2-yl)pyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclohexylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-(butylamino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 S )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclopentylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(2-cyclohexylethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(2-hydroxyethyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(2 R )-2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[(pyrrolidin-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[(pyridin-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclobutylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(2-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(2-cyclopropyl-2-hydroxyethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[3-(trimethylsilyl)propyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({3-[hydroxy(dimethyl)silyl]propyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,3-difluorocyclobutyl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N -[8-fluoro-6-hydroxy-7-(1,1,4-trioxo- ^1λ 6,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene-2-yl] -3-methylbutanimidamide;

5-{8-fluoro-6-hydroxy-2-[3-(oxan-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(7 R )-7-amino-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(4,4-difluorobutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(2-cyclopentylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{( 7R )-7-[(2-cyclobutylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl} ^-1λ6,2,5 -thiadiazolidine -1,1,3-trione;

5-[(7 R )-7-{[2-(3,3-difluorocyclobutyl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(3-methylpentyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(3-ethylpentyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

8-fluoro-6-hydroxy- N -(3-methylbutyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(2-methylpropyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-{8-fluoro-6-hydroxy-2-[3-(pyridin-3-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(1,3,5-trimethyl-1 H -pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(pyrimidin-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(3,5-dimethyl-1 H -pyrazol-4-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[(1,3,5-trimethyl-1 H -pyrazol-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(oxan-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(2-cyclohexyl-2-hydroxyethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3-methoxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(3-aminopropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[3-(piperidin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

tert -butyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate;

5-{8-fluoro-6-hydroxy-2-[(7-oxabicyclo[2.2.1]heptan-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{1-[(1,3,5-trimethyl-1 H -pyrazol-4-yl)methyl]azetidin-3-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(7-oxabicyclo[2.2.1]heptan-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1 H -pyrazol-4-yl]ethyl}-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]methyl}-3,5-dimethyl-1 H -pyrazol-1-yl)-2,2-dimethylpentanenitrile;

5-{8-fluoro-6-hydroxy-2-[(piperidin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[3-(morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(piperidin-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[(1 s ,3 r )-3-(trifluoromethoxy)cyclobutyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[3-(4-methylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[(propan-2-yl)oxy]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({2-[(1 s ,3 r )-3-(trifluoromethoxy)cyclobutyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[(1 s ,3 s )-3-(trifluoromethoxy)cyclobutyl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{1-[(1,3,5-trimethyl-1 H -pyrazol-4-yl)methyl]piperidin-4-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[(1,3,5-trimethyl-1 H -pyrazol-4-yl)methyl]-2-azaspiro[3.3]heptan-6-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(2-{2-[1-(difluoromethyl)-3,5-dimethyl-1 H -pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(bicyclo[2.2.1]heptan-1-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-amino-1-fluoro-3-hydroxy-7-(prop-2-en-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N '-[8-fluoro-6-hydroxy-2-propyl-7-(1,1,4-trioxo- ^1λ 6,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene -2-yl]benzohydrazide;

5-[8-fluoro-6-hydroxy-2-(3-hydroxybutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(2 S )-2-aminopropyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(2 R )-2-aminopropyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(piperazin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{[ rac -(1 R ,2 R )-2-(pyridin-4-yl)cyclopropyl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(2-cyclopentyl-2-methoxyethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[(2 R )-2-amino-4-cyclohexylbutanoyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{3-[(propan-2-yl)oxy]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(1-methyl-1 H -pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1 H -pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[7-amino-1-fluoro-3-hydroxy-7-(4-methylpentyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(7-amino-1-fluoro-3-hydroxy-7-propyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(1,3-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(1,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N -(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-{(7 S )-7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

8-fluoro-6-hydroxy- N -[(oxan-4-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[(3,3-difluorocyclobutyl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -[(oxolan-2-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -(2-cyclopropylethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[(1,3-dimethyl-1 H -pyrazol-5-yl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-{2-[2-(1- tert -butyl-3,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[2-(aminomethyl)-4-fluoro-6-hydroxy-2,3-dihydro- 1H -inden-5-yl]-1λ ^6,2,5 -thiadiazolidine-1,1,3-trione;

5-(4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl)-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-(2-{[bis(3-methylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro- 1H -inden-5-yl)-1λ ^6,2,5 -thiadiazolidine -1,1,3-trione;

8-fluoro-6-hydroxy- N -[(oxolan-3-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[(1,5-dimethyl-1 H -pyrazol-4-yl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -[(1-methyl-1 H -pyrazol-5-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-(2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H - pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(2-{[(3-cyclopropylpropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro- 1H -inden-5-yl)-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-(4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl)-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-{2-[2-(1-ethyl-3,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N -(2,2-dimethylpropyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(3-methoxypropyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(3-methoxy-2,2-dimethylpropyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[2-(dimethylamino)ethyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -[2-(1-methylcyclopropyl)ethyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(2-methoxyethyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -[(oxetan-3-yl)methyl]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

8-fluoro-6-hydroxy- N -(2-phenylethyl)-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[3-(dimethylamino)propyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

5-[2-(3-cyclohexylpropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(7-{[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[3-(2,2-dimethylcyclopropyl)propyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ^6,2,5 -thiadiazolidin- 1,1,3-trione;

5-[(3 S )-5-fluoro-7-hydroxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(7-{[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(2 R )-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl]-1λ ^6.2 ,5-thiadiazolidine-1,1,3-trione;

5-[( 2S )-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl]-1λ ^6.2 ,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(4-methoxybutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{3-[3-(trifluoromethyl)phenyl]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{2-methyl-3-[4-(propan-2-yl)phenyl]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[4-(5,5-dimethyl-1,3-dioxan-2-yl)butyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-6-hydroxy-2-[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-pentyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-2-[3-(4-fluorophenyl)propyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

tert -butyl [(1 r ,4 r )-4-{2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl) -3,4-dihydroisoquinolin-2( 1H )-yl]ethyl}cyclohexyl]carbamate;

5-{2-[3-(4- tert -butylphenyl)propyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[8-fluoro-6-hydroxy-2-(3,5,5-trimethylhexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{8-fluoro-2-[3-(2-fluorophenyl)propyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

3-hydroxybutyl 4,4,8-trifluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate;

5-(2-{[(2-cyclobutylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1 H -inden-5-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(7 R )-1-fluoro-3-hydroxy-7-{[(3 R )-3-hydroxybutyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{(7 R )-1-fluoro-3-hydroxy-7-[(4-hydroxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-6-(3-hydroxy-3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[6-(cyclopropylmethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{6-[(4,4-difluorobutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[6-(4,4-difluorobutoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-6-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[1-fluoro-3-hydroxy-6-(3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{1-fluoro-3-hydroxy-6-[(3-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

tert -butyl (2-{[5-fluoro-7-hydroxy-6-(1,1,4-trioxo- ^1λ 6,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene -2-yl]oxy}ethyl)carbamate;

5-(1-fluoro-3-hydroxy-6-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{6-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1λ ^6,2,5 -thiadiazolidin-1,1,3- trion;

5-[6-(2-aminoethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-{2-[2-(3,5-dimethyl-1 H -pyrazol-4-yl)ethyl]-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

N -(cyclohexylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide;

N -[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide;

5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-(8-fluoro-6-hydroxy-2-{[(2 S )-5-oxopyrrolidin-2-yl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

5-[(3 S )-5-fluoro-7-hydroxy-3-(4-methylpentyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione;

and its pharmaceutically acceptable salt.

[00141] In some embodiments, the compound is 5-{( 7R )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione or a pharmaceutically acceptable salt thereof.

[00142] In some embodiments, the compound is 5-{(7 R )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione.

[00143] In some embodiments, the compound is a pharmaceutically acceptable salt of 5-{( 7R )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione.

[00144] In some embodiments, the connection is

or a pharmaceutically acceptable salt thereof.

[00145] In some embodiments, the connection is

[00146] In some embodiments, a compound disclosed herein is formulated as a pharmaceutically acceptable composition comprising the disclosed compound and a pharmaceutically acceptable carrier.

[00147] In some embodiments, the compound disclosed herein is selected from the compound listed in Table 1.

Table 1: Examples of description connections

Connection Number Structure Connection Number Structure 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325

Methods for obtaining approximate compounds

[00148] The compounds of the present invention can be better understood by the following synthetic schemes and methods, which illustrate mechanisms by which the compounds can be prepared. The compounds of the present invention can be prepared by a variety of synthetic methods. Exemplary synthetic methods are shown in Schemes 1-19, but are not limited thereto. The variables R ¹ , R ^II1 , R ^II1' , R ^III1 , R ² , R ³ , R ^II3 , R ^II3' , R ^III3 , R ⁴ , R ⁵ , R ^II5 , R ^III5 , R ⁶ , R ^II6 , R ^III6 , R ⁷ , R ^II7 , R ^III7 , and R ^a are defined as described in detail herein, for example, in the Summary of the Invention.

Scheme 1: Typical scheme for the synthesis of exemplary compounds of the description

[00149] As shown in Scheme 1, compounds of formula (1-4) can be prepared from compounds of formula (1-1) wherein R ^5* is R ⁵ , R ^II5 , or R ^III5 , R ^6* is R ⁶ , R ^II6 , or R ^III6 , and R ^7* is R ⁷ , R ^II7 , or R ^III7 . Compounds of formula (1-1) prepared as described in the examples and schemes below, wherein PG ¹ is a protecting group such as benzyl, can be reacted in a first step with a preformed mixture of chlorosulfonyl isocyanate and tert -butanol in a solvent such as, but not limited to, cooled (-10-10°C) dichloromethane in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine. The intermediate can then be treated under acidic conditions such as trifluoroacetic acid in dichloromethane or hydrochloric acid in dioxane to give compounds of formula (1-2). Compounds of formula (1-2) can be reacted with an alkoxide base such as sodium methoxide in a solvent such as tetrahydrofuran at or near ambient temperature to give compounds of formula (1-3). The protecting group PG ¹ of compounds of formula (1-3) can be removed to give compounds of formula (1-4). When PG ¹ is a benzyl group, deprotection can be accomplished by catalytic hydrogenation. Compounds of formula (1-4) are compounds of formula (I), formula (II) and formula (III).

Scheme 2: Typical scheme for the synthesis of exemplary compounds of the description

[00150] As shown in Scheme 2, compounds of formula (2-4) can be prepared from compounds of formula (2-1) wherein LG ¹ is a leaving group such as chloro, bromo, iodine, or sulfonate, and PG ¹ is a protecting group such as, but not limited to, benzyl. Compounds of formula (2-1) can be cross-coupled with water under palladium-catalyzed cross-coupling conditions comprising a catalyst or precatalyst, a base such as cesium carbonate, and a heated solvent mixture such as N,N -dimethylformamide and water to provide compounds of formula (2-2). Compounds of formula (2-2) can be alkylated with compounds of formula R ^2a -LG ¹ , where R ^2a is optionally substituted C _1-6 alkyl, C _3-6 cycloalkylC _1-6 alkylene, or (3-6 membered heterocyclyl)C _1-6 alkylene, and LG ¹ is a leaving group such as chloro, bromo, iodine, or sulfonate, in the presence of a base such as cesium carbonate and a solvent such as N,N -dimethylformamide to form compounds of formula (2-3). Compounds of formula (2-3) can be converted to compounds of formula (2-4) using catalytic hydrogenation (130-150 psi) for 30-50 hours in a solvent such as 2,2,2-trifluoroethanol to remove the PG ¹ protecting group and restore the aromatic ring. Alternatively, compounds of formula (2-3) can be deprotected using procedures known to those skilled in the art to yield compounds of formula (2-5). When PG ¹ is benzyl, treatment of compounds of formula (2-3) with boron trichloride in the presence of pentamethylbenzene in cold dichloromethane yields compounds of formula (2-5). Compounds of formula (2-5) can then be converted under catalytic hydrogenation conditions in acetic acid to compounds of formula (2-4). Compounds of formula (2-4) represent compounds of formula (I).

Scheme 3: Typical scheme for the synthesis of exemplary compounds of the description

[00151] As shown in Scheme 3, compounds of formula (3-3) can be prepared from compounds of formula (2-1) wherein LG ¹ is a leaving group such as chlorine, bromine, iodine, or sulfonate, and PG ¹ is a protecting group such as, but not limited to, benzyl. Compounds of formula (2-1) can be cross-coupled with amines of formula R ^3a -NH ₂ , where R ^3a is optionally substituted C _1-6 alkyl, optionally substituted C _1-6 cycloalkylC _1-6 alkylene, optionally substituted 4-6 membered heterocyclyl, optionally substituted (4-6 membered heterocyclyl)C _1-6 alkylene, optionally substituted (5-6 membered heteroaryl)C _1-6 alkylene, or optionally substituted phenyl-C _1-6 alkylene under palladium-catalyzed cross-coupling conditions including a catalyst or precatalyst, a ligand, a base such as cesium carbonate, and a heated solvent such as tert -amyl alcohol, to provide compounds of formula (3-1). Compounds of formula (3-1) can be deprotected as described in Scheme 2 to yield compounds of formula (3-2). Compounds of formula (3-2) can be reduced to compounds of formula (3-3) using catalytic hydrogenation conditions in acetic acid or a mixture of methanol and acetic acid. Compounds of formula (3-3) represent compounds of formula (I).

Scheme 4: Typical scheme for the synthesis of exemplary compounds of the description

[00152] As shown in Scheme 4, compounds of formula (4-3) can be prepared from compounds of formula (2-1) wherein LG ¹ is a leaving group such as chloro, bromo, iodine, or sulfonate, and PG ¹ is a protecting group such as, but not limited to, benzyl. Compounds of formula (2-1) can be deprotected using procedures known to those skilled in the art to provide compounds of formula (4-1). When PG ¹ is benzyl, treatment of compounds of formula (2-1) with boron trichloride in the presence of pentamethylbenzene in cold dichloromethane provides compounds of formula (4-1). Compounds of formula (4-1) can be cross-linked with R ^4a -CH=CH-B(OR ^4b ) ₂ , where -B(OR ^4b ) ₂ is a boronic acid or boronate and R ^4a is optionally substituted C _3-6 cycloalkyl and optionally substituted 4-6 membered heterocyclyl, for example, under Suzuki reaction conditions, to give compounds of formula (4-2). Reduction of compounds of formula (4-2) under catalytic hydrogenation conditions in a solvent such as, but not limited to, 2,2,2-trifluoroethanol gives compounds of formula (4-3). Compounds of formula (4-3) are compounds of formula (I).

Scheme 5: Typical scheme for the synthesis of exemplary compounds of the description

[00153] As shown in Scheme 5, compounds of formula (5-6) can be prepared from compounds of formula (5-1) wherein LG ¹ is a leaving group such as chloro, bromine, iodine, or sulfonate, and PG ¹ is a protecting group such as, but not limited to, benzyl. Compounds of formula (5-1) can be reacted with a base such as lithium 2,2,6,6-tetramethylpiperidin-1-ide in the presence of N,N , N ', N' -tetramethylethylenediamine in a solvent such as cold tetrahydrofuran and then treated with allyl bromide (5-2) to give compounds of formula (5-3). Compounds of formula (5-3) can be treated in a three-step hydroboration-oxidation sequence to give compounds of formula (5-4). Compounds of formula (5-4) can then be reacted under suitable palladium-catalyzed cross-coupling reaction conditions to afford chromans of formula (5-5). Compounds of formula (5-5) can be deprotected using procedures known to those skilled in the art to afford compounds of formula (5-6). When PG ¹ is benzyl, treatment of compounds of formula (5-5) with boron trichloride in the presence of pentamethylbenzene in cold dichloromethane affords compounds of formula (5-6). Compounds of formula (5-6) are compounds of formula (II).

Scheme 6: Typical scheme for the synthesis of exemplary compounds of the description

[00154] As shown in Scheme 6, compounds of formula (6-4) can be prepared from compounds of formula (6-1) wherein LG ¹ is a leaving group such as chloro, bromo, iodine, or sulfonate, and PG ¹ is a protecting group such as, but not limited to, benzyl. Compounds of formula (6-1), prepared analogously to compounds of formula (5-3) in Scheme 5, can be cross-coupled with water to form compounds of formula (6-2). Compounds of formula (6-2) can be reacted with boron trichloride in the presence of pentamethylbenzene in cold dichloromethane to give compounds of formula (6-3). Compounds of formula (6-3) can be cyclized in the presence of a silver salt such as silver trifluoromethanesulfonate to give compounds of formula (6-4). Compounds of formula (6-4) are compounds of formula (II).

Scheme 7: Typical scheme for the synthesis of exemplary compounds of the description

[00155] As shown in Scheme 7, compounds of formula (7-5) can be prepared from compounds of formula (7-1) wherein LG ¹ is a leaving group such as chloro, bromine, iodine, or sulfonate and PG ² is a protecting group such as, but not limited to, (methoxyethoxy)methyl. Compounds of formula (7-1) can be cross-coupled with H ₂ NCH ₂ CO ₂ - t -Bu in the presence of a palladium catalyst, a ligand, and a base to form compounds of formula (7-2). Compounds of formula (7-2) can then be reacted with a preformed mixture of chlorosulfonyl isocyanate and tert-butanol in a solvent such as, but not limited to, cooled dichloromethane, in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine to provide compounds of formula (7-3). Compounds of formula (7-3) can then be reacted with Mg( _OCH3 ) ₂ in methanol in a heated solvent such as 2-methyltetrahydrofuran to give cyclized compounds of formula (7-4). Compounds of formula (7-4) can then be converted to compounds of formula (7-5) by removing the protecting group ^PG2 under conditions known to those skilled in the art and depending on the particular protecting group. When ^PG2 is (methoxyethoxy)methyl, treatment with an acid such as 4 M HCl in dioxane gives compounds of formula (7-5). Compounds of formula (7-5) are compounds of formula (II).

Scheme 8: Typical scheme for the synthesis of exemplary compounds of the description

[00156] As shown in Scheme 8, compounds of formula (8-5) can be prepared from compounds of formula (8-1) wherein LG ¹ is a leaving group such as chloro, bromine, iodine, or sulfonate and PG ² is a protecting group such as, but not limited to, (methoxyethoxy)methyl. Accordingly, compounds of formula (8-1) can be cross-coupled with amines H ₂ NC(R ⁶ )(R ⁷ )CO ₂ - t -Bu under conditions known to those skilled in the art. Subsequent treatment with a pre-prepared mixture of chlorosulfonyl isocyanate and allyl alcohol in a solvent such as chilled dichloromethane provides compounds of formula (8-2). Treatment of compounds of formula (8-2) with tetrakis(triphenylphosphine)palladium(0) in the presence of a base such as sodium methoxide can provide the corresponding 1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione moiety. The dioxolane moiety can then be removed by treatment under acidic conditions such as, but not limited to, formic acid to provide compounds of formula (8-3). Compounds of formula (8-3) can be reductively aminated with amines, (R ^3a )(R ^a )NH, where R ^3a is as described in Scheme 3, to provide compounds of formula (8-4). Alternatively, R ^3a and R ^a and the nitrogen to which they are attached can be joined to form a 4-8 membered heterocycle that can be used for the reductive amination of compounds of formula (8-3). The protecting group PG ² can be removed as known to those skilled in the art and depending on the particular protecting group to yield compounds of formula (8-5). When PG ² is (methoxyethoxy)methyl, treatment with an acid such as 4 M HCl in dioxane yields compounds of formula (8-5). Compounds of formula (8-5) are compounds of formula (I).

Scheme 9: Typical scheme for the synthesis of exemplary compounds of the description

[00157] As shown in Scheme 9, compounds of formula (9-4) can be prepared from compounds of formula (2-1) wherein LG ¹ is a leaving group such as chloro, bromo, iodine, or sulfonate, and PG ¹ is a protecting group such as, but not limited to, benzyl. Compounds of formula (2-1) can be cross-coupled under palladium catalyzed reaction conditions, such as Suzuki conditions, with compounds of formula (9-1) wherein -B(OR ^4b ) ₂ is a boronic acid or boronate, PG ³ is an amine protecting group such as tert -butoxycarbonyl, and "het" is a heterocyclyl containing a nitrogen ring, to provide compounds of formula (9-2). Treatment under catalytic hydrogenation conditions saturates the heterocyclyl ring and removes the protecting group PG ¹ to yield compounds of formula (9-3). Compounds of formula (9-3) can be further reduced under catalytic hydrogenation conditions and the protecting group PG ³ can be removed in a second step to yield compounds of formula (9-4). When PG ³ is tert-butoxycarbonyl, treatment with an acid such as trifluoroacetic acid in dichloromethane is suitable for removing the protecting group. Compounds of formula (9-4) are compounds of formula (I). Compounds of formula (9-4) can be further modified, for example, by alkylation or acylation, to yield additional compounds of formula (I).

Scheme 10: Typical scheme for the synthesis of exemplary compounds of the description

[00158] As shown in Scheme 10, compounds of formula (10-8), formula (10-10), and formula (10-11) can be prepared from compounds of formula (10-1) wherein LG ² is a leaving group such as, but not limited to, chloro, bromo, or iodine and PG ¹ is a protecting group such as, but not limited to, benzyl. Compounds of formula (10-1) can be reacted with compounds of formula (10-2) under reductive amination conditions. Subsequent protection of the resulting amine with a nitrogen protecting group such as, but not limited to, tert -butoxycarbonyl provides compounds of formula (10-3). Compounds of formula (10-3) can be treated with n -butyl lithium to result in cyclization to provide compounds of formula (10-4). The amide nitrogen of compounds of formula (10-4) can be alkylated with bromoacetate BrC(R ^III6 )(R ^III7 )CO ₂ CH ₃ in the presence of a base such as but not limited to 1,2,2,6,6-pentamethylpiperidine in a heated solvent such as heated N,N -dimethylformamide to give compounds of formula (10-5). In a three-step process, the carbonyl can be reduced to the corresponding methylene. In the first step, treatment with a reducing agent such as sodium borohydride gives the corresponding alcohols. The second step is treatment with 1,1'-thiocarbonyldiimidazole (TCDI) in the presence of base to give the corresponding 1H- imidazole-1-carbothioates. The 1H -imidazole-1-carbothioates can be treated with tributyltin hydride and triethylborane in the third step to give the tetrahydroisoquinolines of formula (10-6). Compounds of formula (10-6) can be treated with sodium methoxide in heated methanol to remove the trifluoroacetyl group. Subsequent treatment with a previously prepared mixture of chlorosulfonyl isocyanate and allyl alcohol in a solvent such as chilled dichloromethane gives the alloc-sulfonylurea. Treatment of the alloc-sulfonylurea with tetrakis(triphenylphosphine)palladium(0) in the presence of a base such as sodium methoxide can give the corresponding 1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione moiety of compounds of formula (10-7). Simultaneous removal of the PG ¹ and PG ³ protecting groups gives compounds of formula (10-8). When PG ¹ is benzyl and PG ³ is t -butoxycarbonyl, treatment with boron trichloride in the presence of 1,2,3,4,5-pentamethylbenzene in cold dichloromethane removes both the benzyl and t-butoxycarbonyl groups. Alternatively, the PG ³ protecting group can be selectively removed from compounds of formula (10-7) to give compounds of formula (10-9). When PG ³ is t-butoxycarbonyl, treatment with an acid such as trifluoroacetic acid in dichloromethane gives compounds of formula (10-9). Compounds of formula (10-9) can be treated with carboxylic acids of the formula R ^10a -CO ₂ H, where R ^10a is optionally substituted C _1-6 alkyl, under amide bond forming conditions and then removing PG ¹ to give compounds of formula (10-10). One set of conditions for forming the amide bond involves treatment with tetramethylaminium 2-( 1H- benzotriazol-1-yl)-1,1,3,3-tetrafluoroborate (TBTU) in the presence of a tertiary amine base such as diisopropylethylamine in a solvent such as dichloromethane. When PG ¹ is benzyl, treatment with boron trichloride in the presence of 1,2,3,4,5-pentamethylbenzene in cold dichloromethane removes the benzyl protecting group. Compounds of formula (10-9) can also be alkylated with compounds of formula R ^10b -LG ¹ , where R ^10b is optionally substituted C _1-6 alkyl, optionally substituted -C _1-6 alkylene-C _3-6 cycloalkyl, optionally substituted C _1-6 alkylenephenyl, optionally substituted C _1-6 alkylene-(4- to 6-membered) heterocyclyl, and optionally substituted C _1-6 alkylene-(5- to 6-membered) heteroaryl, and LG ¹ is a leaving group such as chloro, bromo, iodine, or sulfonate, and then deprotected to provide compounds of formula (10-11). One set of alkylation conditions involves treating compounds of formula (10-9) with compounds of formula R ^10b -LG ¹ in the presence of a base such as cesium carbonate in heated acetonitrile. Then, when PG ¹ is benzyl, treatment with boron trichloride in the presence of 1,2,3,4,5-pentamethylbenzene in cold dichloromethane removes the benzyl protecting group and gives compounds of formula (10-11). Compounds of formula (10-8), formula (10-10), and formula (10-11) represent compounds of formula (III).

Scheme 11: Typical scheme for the synthesis of exemplary compounds of the description

[00159] As shown in Scheme 11, compounds of formula (11-2) can be prepared from compounds of formula (10-9), wherein PG ¹ is a protecting group such as, but not limited to, benzyl. Compounds of formula (10-9) can be reacted with compounds of formula R ^11a =O under reductive amination conditions to yield compounds of formula (11-1). R ^11a is optionally substituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-7 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-4-6-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, 4-8 membered heterocycle, -(4-7 membered heterocycle)-C _1-6 alkylene-5-6-membered heteroaryl. R ^11a may be optionally substituted as described for R ^III2 . R ^11a = O is the corresponding aldehyde or the corresponding ketone of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, HC _1-6 alkylene-C _3-7 cycloalkyl, HC _1-6 alkylene-phenyl, HC _1-6 alkylene-4-6-membered heterocyclyl, HC _1-6 alkylene-5-6-membered heteroaryl, 4-8-membered heterocycle, H-(4-7-membered heterocycle)-C _1-6 alkylene-5-6-membered heteroaryl. Compounds of formula (11-1) can be deprotected using methods known to those skilled in the art and depending on the nature of PG ¹ , to yield compounds of formula (11-1). When PG ¹ is benzyl, treatment with boron trichloride in the presence of 1,2,3,4,5-pentamethylbenzene in cold dichloromethane removes the benzyl protecting group to give compounds of formula (11-2). Alternatively, when PG ¹ is benzyl, treatment under catalytic hydrogenation or transfer hydrogenation conditions removes the benzyl protecting group to give compounds of formula (11-2). Compounds of formula (11-1) and compounds of formula (11-2) can be further modified using techniques known to those skilled in the art. Compounds of formula (11-2) represent compounds of formula (III).

Scheme 12: Typical scheme for the synthesis of exemplary compounds of the description

[00160] As shown in Scheme 12, compounds of formula (12-5) can be prepared from compounds of formula (12-1) wherein R ^10b is optionally substituted C _1-6 alkyl, optionally substituted -C _1-6 alkylene-C _3-6 cycloalkyl, optionally substituted C _1-6 alkylenephenyl, optionally substituted C _1-6 alkylene-(4- to 6-membered) heterocyclyl, and optionally substituted C _1-6 alkylene-(5- to 6-membered) heteroaryl. Compounds of formula (12-1) wherein PG ¹ is a protecting group such as benzyl can be converted to compounds of formula (12-2) in a three-step process. Dioxolane can be removed from compounds of formula (12-1) under acidic conditions known to one skilled in the art. Reductive amination can introduce an amino group, -NH ₂ . Reductive amination can be carried out under conditions known to one skilled in the art. One stereoselective set of conditions includes treatment with monobasic sodium phosphate, hydrochloric acid, sec -butylamine, pyridoxal 5-phosphate, and ^Codexis® ATA-025. The resulting amine can be protected as a benzyloxycarbonyl by treatment with benzyl chloroformate in the presence of a base forming a benzyloxycarbonyl, PG ³ , protecting group. Compounds of formula (12-2) can then be converted to compounds of formula (12-3) using the thiadiazolidine trione forming sequence described in Scheme 8. Compounds of formula (12-2) can be alkylated with R ^10b -LG ¹ as described in Scheme 10 to give compounds of formula (12-4). Depending on PG ¹ and PG ^3, the protecting groups of compounds of formula (12-4) can be removed stepwise or simultaneously to obtain compounds of formula (12-5). For example, when PG ¹ is benzyl and PG ³ is benzyloxycarbonyl, treatment with boron trichloride in the presence of pentamethylbenzene in cold dichloromethane simultaneously removes both protecting groups. Compounds of formula (12-5) represent compounds of formula (I).

Scheme 13: Typical scheme for the synthesis of exemplary compounds of the description

[00161] As shown in Scheme 13, compounds of formula (13-2) can be prepared from compounds of formula (10-9). Compounds of formula (10-9) can be reacted with triphosgene in the presence of a base such as, but not limited to, a tertiary amine. Subsequent treatment with an amine, R ^10b -NH ₂ , where R ^10b is optionally substituted C _1-6 alkyl, optionally substituted -C _1-6 alkylene-C _3-6 cycloalkyl, optionally substituted C _1-6 alkylenephenyl, optionally substituted C _1-6 alkylene-(4- to 6-membered) heterocyclyl and optionally substituted C _1-6 alkylene-(5- to 6-membered)heteroaryl provides compounds of formula (13-1). Removal of the protecting group PG ¹ is accomplished using procedures known to those skilled in the art and dependent on PG ¹ . When PG ¹ is benzyl, treatment with boron trichloride in the presence of 1,2,3,4,5-pentamethylbenzene in cold dichloromethane removes the benzyl protecting group and yields compounds of formula (13-2). Compounds of formula (13-2) are compounds of formula (III).

Scheme 14: Typical scheme for the synthesis of exemplary compounds of the description

[00162] As shown in Scheme 14, compounds of formula (14-1) can be prepared from compounds of formula (10-8). Compounds of formula (10-8) can be reacted with compounds of formula R ^11a =O under reductive amination conditions to give compounds of formula (14-1). R ^11a is optionally substituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-7 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-4-6-membered heterocyclyl, -C _1-6 alkylene-5-6-membered heteroaryl, 4-8 membered heterocycle, -(4-7 membered heterocycle)-C _1-6 alkylene-5-6-membered heteroaryl. R ^11a may be optionally substituted as described for R ^III2 . R ^11a = O is the corresponding aldehyde or the corresponding ketone of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, HC _1-6 alkylene-C _3-7 cycloalkyl, HC _1-6 alkylene-phenyl, HC _1-6 alkylene-4-6-membered heterocyclyl, HC _1-6 alkylene-5-6-membered heteroaryl, 4-8-membered heterocycle, H-(4-7-membered heterocycle)-C _1-6 alkylene-5-6-membered heteroaryl. Reductive amination can be carried out with conventional reagents such as sodium cyanoborohydride or sodium borohydride or equivalents on a solid support. Compounds of formula (14-1) can be further modified using techniques known to those skilled in the art. Compounds of formula (14-1) represent compounds of formula (III).

Scheme 15: Typical scheme for the synthesis of exemplary compounds of the description

[00163] As shown in Scheme 15, compounds of formula (15-4) can be prepared from compounds of formula (15-1). Compounds of formula (15-1) can be cross-coupled with water under palladium-catalyzed cross-coupling conditions including a catalyst or precatalyst, an optional ligand, a base such as cesium carbonate, and a heated solvent such as N,N -dimethylacetamide to provide compounds of formula (15-2). Compounds of formula (15-2) can be alkylated with compounds of formula R ^15a -LG ¹ , where R ^15a is optionally substituted C _1-6 alkyl, optionally substituted -C _1-6 alkylene-C _3-6 cycloalkyl, optionally substituted C _1-6 alkylene-phenyl, optionally substituted C _1-6 alkylene-(4- to 6-membered)heterocyclyl and optionally substituted C _1-6 alkylene-(5- to 6-membered)heteroaryl and LG ¹ is a leaving group such as chloro, bromo, iodo or sulfonate, followed by deprotection to provide compounds of formula (15-3). One set of alkylation conditions involves treating compounds of formula (15-2) with compounds of formula R ^15a -LG ¹ in the presence of a base such as cesium carbonate in N,N -dimethylformamide. Then, when PG ¹ is benzyl, treatment with ammonium formate in ethanol in the presence of 10% palladium on carbon removes the benzyl protecting group and gives compounds of formula (15-3). Compounds of formula (15-3) can be reduced with hydrogen (approximately 120 psi) in the presence of 10% palladium on carbon in a solvent such as trifluoroethanol to give compounds of formula (15-4). Compounds of formula (15-4) are compounds of formula (I).

Scheme 16: Typical scheme for the synthesis of exemplary compounds of the description

[00164] As shown in Scheme 16, compounds of formula (16-3) can be prepared from compounds of formula (15-1). Compounds of formula (15-1) can be cross-coupled with amines, R ^16a -NH ₂ , under palladium-catalyzed cross-coupling conditions comprising a catalyst or precatalyst, an optional ligand, a base such as cesium carbonate, and a heated solvent mixture such as N,N -dimethylacetamide to provide compounds of formula (16-1). The protecting group PG ¹ can be removed under conditions known to one skilled in the art and depending on the particular protecting group used. When PG ¹ is benzyl, treatment with boron trichloride in the presence of pentamethylbenzene in cold dichloromethane or, alternatively, treatment under transfer hydrogenation conditions removes the protecting group to give compounds of formula (16-2). Compounds of formula (16-2) can be reduced with hydrogen (approximately 120 psi) in the presence of 10% palladium on carbon in a solvent such as trifluoroethanol to give compounds of formula (16-3). Compounds of formula (16-3) are compounds of formula (I).

Scheme 17: Typical scheme for the synthesis of exemplary compounds of the description

[00165] As shown in Scheme 17, compounds of formula (17-7) can be prepared from compounds of formula (17-1). Compounds of formula (17-1), wherein LG ² is a leaving group such as chloro, bromo, or iodine, and PG ¹ is a protecting group such as benzyl, can be treated with a base such as lithium diisopropylamide, followed by oxathiazolidine 2,2-dioxide of formula (17-2), wherein Boc is tert -butoxycarbonyl and R ^17a is optionally substituted alkyl, optionally substituted -C _1-6 alkylene-C _3-6 cycloalkyl, or optionally substituted -C _1-6 alkylene-4-6-membered heterocyclyl, to form compounds of formula (17-3). Compounds of formula (17-3) can be alkylated with methyl bromoacetate in the presence of base and potassium iodide. Cross-coupling with potassium vinyl trifluoroborate then affords compounds of formula (17-4). Compounds of formula (17-4) can be oxidized to the corresponding aldehyde with potassium osmate dihydrate in the presence of N -methylmorpholine N -oxide and sodium metaperiodate. The intermediate aldehyde can be cyclized with triethylsilane in the presence of boron trifluoride diethyl etherate to afford compounds of formula (17-5). The trifluoroacetamide group can be removed from compounds of formula (17-5) by treatment with sodium methoxide. Thiadiazolidinium trione can be prepared following the steps described in Scheme 8 to afford compounds of formula (17-6). The protecting groups, Boc and PG ¹ , can be removed from compounds of formula (17-6) simultaneously or stepwise depending on PG ¹ using conditions known to one skilled in the art to produce compounds of formula (17-7). For example, when PG ¹ is benzyl, transfer hydrogenation selectively removes PG ¹ . Subsequent exposure to hydrochloric acid in dioxane will remove the tert-butoxycarbonyl protecting group. Compounds of formula (17-7) are compounds of formula (I).

Scheme 18: Typical scheme for the synthesis of exemplary compounds of the description

[00166] As shown in Scheme 18, compounds of formula (18-7) and compounds of formula (18-8) can be prepared from compounds of formula (18-1). Compounds of formula (18-1), wherein PG ¹ is a protecting group such as benzyl, can be converted to compounds of formula (18-2) in a three-step process. Treatment of compounds of formula (18-1) under cross-coupling reaction conditions gives a bicyclic structure. The benzyl group can be selectively removed from the tetrahydroisoquinoline nitrogen by treatment with 1-chloroethyl chloroformate and 8-bis(dimethylamino)naphthalene in a solvent such as 1,2-dichloroethane. The exposed amine can be protected as tert -butoxycarbonyl by treatment with di- tert -butyl dicarbonate in the presence of a base such as sodium bicarbonate in a solvent such as a mixture of tetrahydrofuran and water. Compounds of formula (18-2) can be oxidized with osmium tetroxide and sodium periodate to give the corresponding ketone, a compound of formula (18-3). Compounds of formula (18-3) can be treated with diethylaminosulfur trifluoride (DAST) to convert the ketone to the corresponding difluoromethylene. Subsequent treatment with potassium carbonate in methanol removes the trifluoroacetyl moiety to give compounds of formula (18-4). Compounds of formula (18-4) can be treated as described in Scheme 8 to form the thiadiazolidine trione, giving compounds of formula (18-5). The tert -butoxycarbonyl protecting group can be removed from compounds of formula (18-5) by treatment under acidic conditions, such as trifluoroacetic acid in dichloromethane, to give compounds of formula (18-6). Compounds of formula (18-6) can be reductively aminated and then deprotected using procedures known to one skilled in the art to provide compounds of formula (18-7), wherein R ^18a is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-7-membered heterocyclyl, -C _1-6 alkylene-C _3-8 cycloalkyl, -C _1-6 alkylene-phenyl, -C _1-6 alkylene-4-7-membered heterocyclyl, or -C _1-6 alkylene-5-6-membered heteroaryl. Compounds of formula (18-6) can also be converted to compounds of formula (18-8). Compounds of formula (18-6) can be treated with 4-nitrophenyl carbonochloridate in the presence of a tertiary amine base. Then treatment with an alcohol R ^18b -OH, where R ^18b is optionally substituted C _1-6 alkyl, in the presence of a base such as potassium tert -butoxide, followed by removal of the protecting group PG ¹ gives compounds of formula (18-8). Compounds of formula (18-7) and formula (18-8) represent compounds of formula (III).

Scheme 19: Typical scheme for the synthesis of exemplary compounds of the description

[00167] As shown in Scheme 19, compounds of formula (19-2) can be prepared from compounds of formula (19-1). Compounds of formula (19-1) can be prepared as described in the examples. Compounds of formula (19-1) can be reductively aminated with an aldehyde or ketone (R ^19a =O) under conditions known to one skilled in the art to provide compounds of formula (19-2). R ^19a is -C _1-6 alkyl, -C _1-6 alkylene-N(R ^a )-C _1-6 alkyl, -C _1-6 alkylene-N( ^{R a} ₎ -C _1-6 alkylene-C _3-6 cycloalkyl, _{C 3-6} cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl or -C _1-6 alkylene-4-6-membered heterocyclyl, in which each moiety may be optionally substituted. Compounds of formula (19-2) are compounds of formula (I).

Pharmaceutical compositions

[00168] Provided herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of formula (I), formula (II), or formula (III). In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments, a compound disclosed herein, e.g., a compound of formula (I), formula (II), or formula (III), is present in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[00169] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Typically, such preparative methods include the steps of bringing into association the disclosed compound (the "active ingredient") with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into the desired single or multi-dose unit. The pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, in single unit dose form, and/or in multiple single unit dose form. The term "unit dose" as used herein means a discrete quantity of a pharmaceutical composition containing a predetermined quantity of the active ingredient. The quantity of active ingredient is typically equal to the dosage of the active ingredient to be administered to a subject, and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[00170] The relative amounts of a compound disclosed herein, such as a compound of formula (I), formula (II), or formula (III), a pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the present disclosure will vary depending on the identity, size, and/or condition of the subject being treated, and further depending on the route by which the composition is to be administered. As an example, a composition may contain from 0.1% to 100% (w/w) of a compound described herein.

[00171] The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not interfere with the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients used in the manufacture of the pharmaceutical compositions of the present disclosure are any of those well known in the pharmaceutical formulation art and include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binders, preservatives, buffering agents, lubricating agents, and/or oils. Pharmaceutically acceptable excipients used in the manufacture of the pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated fatty acids of plant origin, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylenepolyoxypropylene block polymers, polyethylene glycol and wool fat.

[00172] The compositions of the present invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some embodiments, the compounds or compositions of the invention are administered intravenously and/or orally.

[00173] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present disclosure can be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[00174] The pharmaceutically acceptable compositions of this disclosure can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents such as magnesium stearate are also commonly added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added. In some embodiments, the provided oral formulation is formulated for immediate release or sustained/delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. The compound disclosed herein may also be in microencapsulated form.

[00175] The compositions of the present invention can be delivered transdermally, topically in the form of applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, wafers, gels, syrups, suspensions, slurries and the like, suitable for ingestion by a patient. Solid form preparations include powders, tablets, pills, capsules, wafers, suppositories and dispersible granules. Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions. The compositions of the present disclosure can further include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. These components are discussed in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5212,162; and 4,861,760. The entire disclosures of these patents are herein incorporated by reference for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres that are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed . 7:623-645, 1995; as biodegradable injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol . 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present disclosure can be delivered using liposomes that fuse with the cell membrane or are endocytosed, such as using receptor ligands attached to the liposomes that bind to receptors on cell surface membrane proteins, resulting in endocytosis. By using liposomes, particularly if the liposome surface bears receptor ligands specific for target cells or is otherwise preferentially targeted to a particular organ, delivery of the compositions of the present disclosure to target cells in vivo can be focused. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol . 6:698-708, 1995; Ostro, J. Hosp. Pharm . 46: 1576-1587, 1989). The compositions of the present disclosure can also be delivered as nanoparticles.

[00176] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of the present disclosure can also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[00177] In some embodiments, in order to prolong the action of a drug, it is often desirable to slow the absorption of the drug upon subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor solubility in water. The rate of absorption of the drug then depends on the rate of its dissolution, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered dosage form is achieved by dissolving or suspending the drug in an oil vehicle.

[00178] Although the descriptions of pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions that are suitable for administration to humans, one skilled in the art will recognize that such compositions are generally suitable for administration to animals of all species. Modification of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to various animals is well understood, and a veterinary pharmacologist of ordinary skill can devise and/or perform such modifications using routine experimentation.

[00179] The compounds provided herein, for example a compound of formula (I), formula (II), or formula (III), are typically formulated in unit dosage form, for example a unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily use of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dosage level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the potency of the particular active ingredient employed; the particular formulation employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the particular active ingredient employed; the duration of treatment; drugs employed in combination or concurrently with the particular active ingredient employed; and like factors well known in the medical art.

[00180] The precise amount of compound required to achieve an effective amount will vary from subject to subject, depending on, for example, the species, age, and general condition of the subject, the severity of the adverse effects or disorder, the identity of the particular compound(s), the mode of administration, and the like. The desired dose may be administered three times daily, twice daily, once daily, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In some embodiments, the desired dose may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[00181] It should be understood that the dosage ranges described herein provide guidance on the administration of the provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or adolescent can be determined by a practitioner or person skilled in the art and may be lower or the same as the amount administered to an adult.

[00182] It will also be understood that a compound or composition disclosed herein can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or alter their distribution in the body. It will also be understood that the therapy employed may achieve the desired effect for the same disorder and/or may achieve different effects.

[00183] The compound or composition can be administered simultaneously with, before, or after one or more additional pharmaceutical agents, which can be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent can be administered at a dose and/or schedule determined for that pharmaceutical agent. Additional pharmaceutical agents can also be administered together with each other and/or with a compound or composition described herein at a single dose or administered separately at different doses. The specific combination for use in the regimen will take into account the compatibility of the compound of the invention with the additional pharmaceutical agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that additional pharmaceutical agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels used individually.

[00184] Examples of additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration under the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules associated with proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[00185] The pharmaceutical compositions provided herein include compositions in which the active ingredient (e.g., the compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., an amount effective to achieve the intended purpose. The actual amount effective for a particular application will depend on, among other things, the condition being treated. When administered in methods for treating a disease, such compositions will contain an amount of the active ingredient effective to achieve the desired result, such as inhibiting the activity of a target molecule (e.g., PTPN2 and/or PTPN1) and/or reducing, eliminating, or slowing the progression of disease symptoms. Determination of a therapeutically effective amount of a compound disclosed herein is within the ability of those skilled in the art, particularly in light of the detailed description herein.

[00186] The dosage and frequency (single or multiple) administered to a mammal may vary depending on a variety of factors, such as whether the mammal suffers from another disease and the route of administration; the size, age, sex, health status, body weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated, the type of concomitant treatment, complications caused by the treatment, or other health-related problems. Other therapeutic regimens or agents may be used in combination with the methods, compounds, and compositions described herein. Adjustment and variation of established dosages (e.g., frequency and duration) are readily available to those skilled in the art.

[00187] For any compound described herein, a therapeutically effective amount can be initially determined using cell culture assays. Target concentrations will be those concentrations of the active compound(s) that can be achieved by the methods described herein, when measured using methods described herein or known in the art.

[00188] As is well known in the art, therapeutically effective amounts for use in humans can also be determined in animal models. For example, a dose for humans can be designed to achieve a concentration that has been found to be effective in animals. The dosage for humans can be adjusted by monitoring the effectiveness of the compounds and adjusting the dosage upward or downward as described above. Adjusting the dose to achieve maximum effectiveness in humans based on the methods described above and other methods is within the capabilities of one of ordinary skill in the art.

[00189] Dosages may vary depending on the requirements of the patient and the compound being administered. The dose administered to the patient, as used herein, should be sufficient to effect a positive therapeutic response in the patient over time. The size of the dose will also depend on the presence, nature, and extent of any adverse effects. Determination of the correct dosage for a particular situation is within the competence of the practitioner. Typically, treatment is initiated with smaller doses that are less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect is achieved under the particular circumstances. Dose amounts and intervals may be individually adjusted to provide levels of the compound administered that are effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is proportionate to the severity of the patient's disease state.

[00190] Using the teachings presented herein, it is possible to plan an effective prophylactic or therapeutic treatment regimen that does not cause significant toxicity and is still effective in treating the clinical symptoms exhibited by a particular patient. This planning should include careful selection of the active compound, taking into account factors such as compound potency, relative bioavailability, patient body weight, the presence and severity of adverse side effects, the preferred route of administration, and the toxicity profile of the selected agent.

[00191] The present invention also includes kits ( e.g. , pharmaceutical packages). The kits provided herein may be useful for preventing and/or treating a disease ( e.g. , cancer, type 2 diabetes, obesity, metabolic disease, or other disease or condition described herein).

[00192] The provided kits may comprise a pharmaceutical composition or compound of the invention and a container (e.g., a vial, ampoule, bottle, syringe, and/or dosage package, or other suitable container). In some embodiments, the provided kits may optionally further comprise a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the invention. In some embodiments, the pharmaceutical composition or compound of the invention contained in the container and the second container are combined to form a single unit dosage form.

[00193] Thus, in one aspect, kits are provided comprising a first container comprising a compound disclosed herein. In some embodiments, the kits are useful for preventing and/or treating a proliferative disease in a subject. In some embodiments, the kits further comprise instructions for administering the disclosed compound to a subject to prevent and/or treat a disease described herein.

Treatment methods

[00194] Disclosed herein are compounds, compositions, and methods comprising a compound described herein, such as a compound of Formula (I), Formula (II), or Formula (III). In some embodiments, the compounds, compositions, and methods described herein are used to prevent or treat a disease, disorder, or condition. Examples of diseases, disorders, or conditions include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic disorder.

Cancer

[00195] In some embodiments, a compound described herein, such as a compound of Formula (I), Formula (II), or Formula (III), is used to treat cancer. As used herein, the term "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, cancer of the kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testicle, glioma, esophagus, liver including hepatocarcinoma, lymphoma including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and/or multiple myeloma. In some additional cases, "cancer" refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[00196] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals, including leukemia, lymphoma, carcinomas, and sarcomas. Examples of cancers that can be treated with the compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma or melanoma. Additional examples include thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant insulinoma of the pancreas, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, neoplasms endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the papilla, phyllodes tumors, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, or prostate cancer.

[00197] The term "leukemia" refers broadly to progressive malignant diseases of the blood-forming organs and is typically characterized by abnormal proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is usually classified based on (1) the duration and nature of the disease - acute or chronic; (2) the type of cell involved - myeloid (myelogenous), lymphoid (lymphogenic), or monocytic; and (3) whether there is an increase or absence of an increase in the number of abnormal cells in the blood - leukemia or aleukemia (subleukemia). Examples of leukemias that can be treated with the compound, pharmaceutical composition or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, cellular lymphosarcoma leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblast leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Reeder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[00198] The term "sarcoma" generally refers to a tumor that is composed of a substance similar to embryonic connective tissue and is usually composed of tightly packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that can be treated with the compound, pharmaceutical composition or method provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemeti's sarcoma, adipose tissue sarcoma, liposarcoma, alveolar sarcoma of the soft part, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma B-cell lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocyte sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[00199] The term "melanoma" means a tumor arising from the melanocytic system of the skin and other organs. Melanomas that can be treated with the compound, pharmaceutical composition or method provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passy melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma or superficial spreading melanoma.

[00200] The term carcinoma refers to a malignant neoplasm composed of epithelial cells that have a tendency to invade surrounding tissues and cause metastasis. Examples of carcinomas that can be treated with the compound, pharmaceutical composition or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortex carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basocellular carcinoma, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedonic carcinoma, carcinoma of the body, cribriform carcinoma, carcinoma en cuirasse, carcinoma of the skin, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, ductal carcinoma, solid carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitsky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanotic carcinoma, carcinoma of the palate, mucinous carcinoma, carcinoma muciparum, mucocellular carcinoma, mucoepidermoid carcinoma, carcinoma of the mucous membrane, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, spiny cell carcinoma, tumor-like carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotic carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongiform carcinoma, squamous cell carcinoma, squamous cell carcinoma, stringy carcinoma, telangiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, tuberous carcinoma, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[00201] In some embodiments, a compound described herein, such as a compound of Formula (I), Formula (II), or Formula (III), is used to treat pancreatic cancer, breast cancer, multiple myeloma, secretory cell cancer. For example, the methods defined herein treat cancer by reducing or decreasing or preventing the occurrence, growth, metastasis, or progression of cancer. In some embodiments, the methods described herein can be used to treat cancer by reducing or eliminating a symptom of cancer. In some embodiments, a compound described herein, such as a compound of Formula (I), Formula (II), or Formula (III), can be used as a single agent in a composition or in combination with another agent in a composition to treat a cancer described herein (e.g., pancreatic cancer, breast cancer, multiple myeloma, secretory cell cancer).

[00202] In some embodiments, compounds (compounds described herein, e.g., a compound of Formula (I), Formula (II), or Formula (III)) and compositions (e.g., compositions comprising a compound described herein, e.g., a compound of Formula (I), Formula (II), or Formula (III)) are used with a cancer immunotherapy (e.g., a checkpoint blocking antibody) to treat a subject (e.g., a human), e.g., having a disease or disorder described herein (e.g., an abnormal cell growth, e.g., a cancer (e.g., a cancer described herein)). The methods described herein comprise administering a compound described herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), and immunotherapy to a subject having an abnormal cell growth, such as a cancer. Examples of immunotherapy include, but are not limited to, the following.

[00203] In some embodiments, the immunotherapeutic agent is a compound (e.g., a ligand, an antibody) that inhibits an immune checkpoint blockade pathway. In some embodiments, the immunotherapeutic agent is a compound that inhibits the indoleamine 2,3-dioxygenase (IDO) pathway. In some embodiments, the immunotherapeutic agent is a compound that agonizes the STING pathway. Cancer immunotherapy is the use of the immune system to treat cancer. Three groups of immunotherapies used to treat cancer include cell-based, antibody-based, and cytokine-based therapies. All groups utilize the display of subtly different structures (e.g., molecular structure; antigens, proteins, molecules, carbohydrates) on the surface of cancer cells that can be detected by the immune system. Cancer immunotherapy (e.g., antitumor immunotherapy or antitumor immunotherapeutic agents) includes, but is not limited to, immune checkpoint antibodies (e.g., PD-1 antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA-4 antibodies, TIM3 antibodies, LAG3 antibodies, TIGIT antibodies); and cancer vaccines (e.g., tumor vaccines or neoantigen-based vaccines such as peptide or RNA vaccine).

[00204] Cell therapy (e.g., cancer vaccines) typically involves removing immune cells from a subject with cancer, either from the blood or from a tumor. Tumor-specific immune cells will be activated, grown, and returned to the subject with cancer, where the immune cells provide an immune response against the cancer. Cell types that can be used in this manner include, for example, natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, dendritic cells, CAR-T therapies (e.g., chimeric antigen receptor T cells, which are T cells engineered to target specific antigens), TIL therapy (e.g., administration of tumor-infiltrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines. An example of cell therapy is Provenge. In some embodiments, the cell therapy is CAR-T therapy.

[00205] Interleukin-2 and interferon-alpha are examples of cytokines, proteins that regulate and coordinate the behavior of the immune system.

Cancer vaccines with neoantigens

[00206] Neoantigens are antigens encoded by tumor-specific mutated genes. Technological innovations have allowed the analysis of the immune response to patient-specific neoantigens arising from tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a key factor in the performance of clinical immunotherapies. These observations suggest that neoantigen load may form a biomarker for cancer immunotherapy. Many new therapeutic approaches are being developed that selectively enhance T cell reactivity against this class of antigens. One approach to targeting neoantigens is cancer vaccines. These vaccines can be developed using peptides or RNA, such as synthetic peptides or synthetic RNA.

[00207] Antibody therapy is the use of antibody proteins produced by the immune system to bind to a target antigen on the surface of a cell. Antibodies are typically encoded by an immunoglobulin gene or genes or fragments thereof. In normal physiology, antibodies are used by the immune system to fight pathogens. Each antibody is specific to one or more proteins, and those that bind to cancer antigens are used, for example, to treat cancer. Antibodies are capable of specifically binding an antigen or epitope (Fundamental Immunology, ^3rd Edition, Paul, WE, ed., Raven Press, NY (1993). Specific binding occurs to the relevant antigen or epitope even in the presence of a heterogeneous population of proteins and other biological substances. Specific binding of an antibody indicates that it binds to its target antigen or epitope with an affinity that is substantially greater than its binding to irrelevant antigens. The relative difference in affinity is often at least 25% greater, more commonly at least 50% greater, and usually at least 100% greater. The relative difference may be at least 2-fold, at least 5-fold, at least 10-fold, at least 25-fold, at least 50-fold, at least 100-fold, or at least 1000-fold, for example.

[00208] Examples of antibody types include, but are not limited to, human, humanized, chimeric, monoclonal, polyclonal, single chain, antibody-binding fragments, and diabodies. Once bound to a cancer antigen, antibodies can induce antibody-dependent cellular cytotoxicity, activate the complement system, prevent interaction of a receptor with its ligand, or deliver a chemotherapy or radiation payload, all of which can result in cell death. Examples of antibodies for the treatment of cancer include, but are not limited to, Alemtuzumab, Bevacizumab, Bretuximab vedotin, Cetuximab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Ipilimumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, Nivolumab, Pembrolizumab, Avelumab, Durvalumab, and Pidilizumab.

Checkpoint blocking antibodies

[00209] The methods described herein include, in some embodiments, treating a human subject suffering from a disease or disorder described herein, a method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a compound (e.g., an inhibitor or antibody) that inhibits an immune checkpoint blockade pathway. Immune checkpoint proteins, under normal physiological conditions, maintain self-tolerance (e.g., prevent autoimmunity) and protect tissues from damage when the immune system responds to, for example, a pathogenic infection. Immune checkpoint proteins can be deregulated by tumors as an important mechanism of immune resistance (Pardoll, Nature Rev. Cancer , 2012, 12, 252-264). Co-stimulatory receptor agonists or inhibitory signaling antagonists (e.g., immune checkpoint proteins) provide enhancement of antigen-specific T-cell responses. Immune checkpoint blocking antibodies do not directly target tumor cells but typically target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

[00210] Examples of checkpoint blocking antibodies include, but are not limited to, anti-CTLA-4, anti-PD-1, anti-LAG3 (e.g., anti-lymphocyte activation gene 3 antibodies), and anti-TIM3 (e.g., anti-T-cell membrane protein 3 antibodies). Examples of anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. Examples of anti-PD-1 ligands include, but are not limited to, PD-L1 (e.g., B7-H1 and CD274) and PD-L2 (e.g., B7-DC and CD273). Examples of anti-PD-1 antibodies include, but are not limited to, nivolumab (e.g., MDX-1106, BMS-936558, or ONO-4538), CT-011, AMP-224, pembrolizumab (trade name Keytruda), and MK-3475. Exemplary PD-L1-specific antibodies include, but are not limited to, BMS936559 (e.g., MDX-1105), MEDI4736, and MPDL-3280A. Examples of checkpoint blockade antibodies also include, but are not limited to, IMP321 and MGA271.

[00211] T-regulatory cells ( e.g. , CD4+, CD25+, or T-reg) are also involved in controlling the distinction between self and non-self (e.g., foreign) antigens and may represent an important mechanism for suppressing the immune response in many cancers. T-reg cells can either arise from the thymus (e.g., "natural T-reg") or can differentiate from mature T cells under conditions of peripheral tolerance induction (e.g., "induced T-reg"). Therefore, strategies that minimize the action of T-reg cells might be expected to promote the immune response to tumors.

IDO pathway inhibitors

[00212] The IDO pathway regulates the immune response by suppressing T cell function and allowing local tumor evasion. IDO expression by antigen-presenting cells (APCs) can deplete tryptophan and, as a result, energize antigen-specific T cells and recruit regulatory T cells. Some tumors even express IDO to protect themselves from the immune system. A compound that inhibits IDO or the IDO pathway activates the immune system to attack cancer (e.g., a subject's tumor). Examples of IDO pathway inhibitors include indoximod, epacadostat, and EOS200271.

STING pathway agonists

[00213] Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Evidence indicates that the STING pathway is involved in the induction of antitumor immune responses. For example, activation of the STING-dependent pathway in cancer cells can lead to tumor infiltration by immune cells and modulation of the antitumor immune response. STING agonists are under development as a class of anticancer agents. Examples of STING agonists include MK-1454 and ADU-S100.

Costimulatory antibodies

[00214] The methods described herein include, in some embodiments, treating a human subject suffering from a disease or disorder described herein, a method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a costimulatory inhibitor or an antibody. In some embodiments, the methods described herein include depletion or activation of anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, and anti-CD40, and variants thereof.

[00215] The methods of the present disclosure involve single as well as multiple administrations of a therapeutically effective amount of a compound as described herein. Compounds, such as a compound described herein, can be administered at regular intervals depending on the nature, severity, and extent of the subject's condition. In some embodiments, a compound described herein is administered in a single dose. In some embodiments, a compound described herein is administered in multiple doses.

Metabolic diseases

[00216] In some embodiments, a compound described herein, such as a compound of Formula (I), Formula (II), or Formula (III), is used to treat a metabolic disease. As used herein, the term "metabolic disease" refers to a disease or condition that affects a metabolic process in a subject. Examples of metabolic diseases that can be treated with a compound described herein, such as a compound of Formula (I), Formula (II), or Formula (III), include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., type I diabetes, type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

[00217] In some embodiments, a compound described herein, such as a compound of Formula (I), Formula (II), or Formula (III), is used to treat a metabolic disease (e.g., a metabolic disease described herein) by reducing or eliminating a symptom of the disease. In some embodiments, the method of treating comprises reducing or eliminating a symptom including high blood pressure, high blood sugar, weight gain, fatigue, blurred vision, abdominal pain, bloating, constipation, diarrhea, jaundice, and the like. In some embodiments, a compound disclosed herein, such as a compound of Formula (I), Formula (II), or Formula (III), can be used as a single agent in a composition or in combination with another agent in a composition to treat a metabolic disorder.

[00218] In some embodiments, the compounds disclosed herein are provided as pharmaceutical compositions comprising a disclosed compound, e.g., Formula (I), Formula (II), or Formula (III), and a pharmaceutically acceptable excipient. In embodiments of the method, a disclosed compound, e.g., Formula (I), Formula (II), or Formula (III), is co-administered with a second agent (e.g., a therapeutic agent). In other embodiments of the method, a disclosed compound, e.g., Formula (I), Formula (II), or Formula (III), is co-administered with a second agent (e.g., a therapeutic agent) that is administered in a therapeutically effective amount.

Combination therapy

[00219] Provided herein is a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), and a second agent (e.g., a second therapeutic agent). In some embodiments, the pharmaceutical composition comprises a second agent (e.g., a second therapeutic agent) in a therapeutically effective amount. In some embodiments, the second agent is an agent for treating cancer, a metabolic disease (e.g., type 2 diabetes or obesity), or a disease or disorder that responds favorably to treatment with PTPN2 or PTPN1 inhibitors.

[00220] The compounds described herein may be used in combination with each other, with other active agents known to be useful in the treatment of cancer, a metabolic disease (e.g., type 2 diabetes or obesity), or a disease or disorder that responds favorably to treatment with PTPN2 or PTPN1 inhibitors, or with additional agents that may not be effective on their own but may contribute to the effectiveness of the active agent.

[00221] In some embodiments, co-administration comprises administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration comprises administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulating, i.e., preparing a single pharmaceutical composition comprising both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or auxiliary agents can be linked or conjugated to each other. In some embodiments, the compounds described herein can be combined with treatment of cancer, a metabolic disease (e.g., type 2 diabetes or obesity), or a disease or disorder that responds favorably to treatment with PTPN2 or PTPN1 inhibitors. In embodiments, the second agent is an anticancer agent. In embodiments, the second agent is a chemotherapeutic agent. In embodiments, the second agent is an agent for treating a metabolic disease. In embodiments, the second agent is an antidiabetic agent. In some embodiments, the second agent is an antiobesity agent.

Anticancer agents

[00222] "Anti-cancer agent" is used in its simple, conventional meaning and refers to a composition (e.g., a compound, a drug, an antagonist, an inhibitor, a modulator) having anti-tumor properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent identified herein that has use in methods of treating cancer. In some embodiments, the anti-cancer agent is an agent approved by the FDA or a similar regulatory agency of a country other than the United States for the treatment of cancer. Examples of anticancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g. mechlorethamine, cyclophosphamide, chlorambucil, meifalan), ethyleneimine and methylmelamines (e.g. hexamethylmelamine, thiotepa), alkyl sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomustine, semustine, streptozocin), triazenes (decarbazine), antimetabolites (e.g. 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folate analogue (e.g. methotrexate) or pyrimidine analogues (e.g. fluorouracil, floxuridine, cytarabine), purine analogues (e.g. mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g. vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g. irinotecan, topotecan, amsacrine, etoposide (VP 16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g. doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g. mitoxantrone), substituted urea (e.g. hydroxyurea), methylhydrazine derivative (e.g. procarbazine), adrenocortical suppressor (e.g. mitotane, aminoglutethimide), epipodophyllotoxins (eg, etoposide), antibiotics (eg, daunorubicin, doxorubicin, bleomycin), enzymes (eg, L-asparaginase), mitogen-activated protein kinase signaling inhibitors (eg, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (eg, rituxan), gossifol, genazen, polyphenol E, chlorfusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemquitabicin, imatinib (Gleevec.RTM.), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 1 1-7082, PKC412, PD184352, 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; D antagonist; G antagonist; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen, prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorines; benzoylstaurosporine; beta-lactam derivatives; beta-aletin; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnaphid; bistraten A; bizelesin; breflat; bropirimine; budotitan; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canaripox IL-2; capecitabine; carboxamide-aminotriazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chlorquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambecidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanethraquinones; cycloplatam; cypemycin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; halocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfame; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplakt; irsogladine; isobengazole; isohomochalicordrine B; itazetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribin; lurtotecan; lutetium texaphyrin; lysophylline; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirmostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin, fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A + myobacterial cell wall sk; mopidamole; multidrug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard antitumor agent; mycoperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavine; nafterpine; narthragrastim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nizamycin; nitric oxide modulators; nitroxide antioxidant; nitrulline; 06-benzylguanine; octreotide; oxycenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoyl rhizoxin; pamidronic acid; panaxytriol; panomifen; parabactin; pazelliptin; pegaspargase; peldesin; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perphosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; pyritrekem; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum triamine complex; sodium porfimer; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immunomodulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin-polyoxyethyl conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptin demethylated; rhenium etidronate Re 186; rhizoxin; ribozymes; RII retinamide; roglethimide; rohitukin; romurtide; roquinimex; rubiginone Bl; ruboxil; safingol; sentopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single-chain antigen-binding protein; sizofuran; sobuzoxan; sodium borocaptate; sodium phenylacetate; solverol; somatomedin-binding protein; sonermin; sparphonic acid; spikamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; thallimustine; tamoxifen methiodide; tavromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrilium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlordecaoxide; tetrazomine; taliblastine; thiocoralin; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinane; thyroid stimulating hormone; tin ethyl etiopurpurine; tirapazamine; titanocene dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramin; verdens; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanotherone; zeniplatin; zilascorb; stimalamer of cynostatin, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelezin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; karacemid; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelezin; cedefingol; chlorambucil; cyrolemycin; cladribine; cristnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; desaguanine; desaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flucitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imofosine; interleukin II (including recombinant interleukin II or r1L.sub.2), interferon alpha-2a; interferon alpha-2b; interferon alpha-nl; interferon alpha-n3; interferon beta-la; interferon gamma-lb; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromine; mitogilline; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestan; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; roglethimide; safingol; safingol hydrochloride; semustine; simtrazen; sodium sparfosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribin phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; Zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate microtubule formation or stability (e.g., Taxol, i.e., paclitaxel), Taxotere, compounds that make up the taxane skeleton, Erbulozole (i.e., R-55104), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobulin isethionate (i.e., as CI-980), Vincristine, NSC-639829, Discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), Altorhirtins (e.g., Altorhirtin A and Altorhirtin C), Spongistatins (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), semadotin hydrochloride (e.g. LU-103793 and SC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e. deoxypothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB and deoxypothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Deoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578 (Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-1 12378 (Aventis), Vincristine Sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena) RPR-258062A), Vitilevuamide, Tubulisin A, Canadensol, Centaureadin (i.e. NSC-106969), T-138067 (Tularik, i.e. T-67, TL-138067, and TI- 138067), COBRA-1 (Parker Hughes Institute, i.e. DDE-261 and WHI-261), H10 (University of Kansas), H16 (University of Kansas), Oncocidin A 1 (e.g. BTO-956 and DIME), DDE- 313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Noscapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-191), TMPN (Arizona State University), Vanadocene Acetyl Lactate, T-138026 (Tularik), Monsatrol, Inanocine (i.e. NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobins (such as desmethyleleutherobin, desaethyleleutherobin, isoeleutherobin A, and Z-eleutherobinide), Caribeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccolanolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylachistin (i.e., NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resveratrol sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-25041 1 (Sanofi), steroids (eg, dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone (GnRH) agonists such as goserelin or leuprolide, adrenocorticosteroids (eg, prednisone), progestins (eg, hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g. diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g. tamoxifen), androgens (e.g. testosterone propionate, fluoxymesterone), antiandrogen (e.g. flutamide), immunostimulants (e.g. Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha interferon, etc.), monoclonal antibodies (e.g. anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR and anti-VEGF monoclonal antibodies), immunotoxins (e.g. calicheamicin conjugate-monoclonal antibody to CD33, pseudomonas exotoxin conjugate-monoclonal antibody to CD22, etc.), radioimmunotherapy (e.g. monoclonal antibody to CD20, conjugated with ^{U 1} ln, ⁹⁰ Y or ¹³¹ I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutics (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib or the like.

[00223] The term "chemotherapeutic" or "chemotherapeutic agent" is used in accordance with its ordinary meaning and refers to a chemical compound or compound that has antitumor properties or the ability to suppress the growth or proliferation of cells.

[00224] Additionally, the compounds described herein can be co-administered with conventional immunotherapeutic agents, including, but not limited to, immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., calicheamicin conjugate of an anti-CD33 monoclonal antibody, pseudomonas exotoxin conjugate of an anti-CD22 monoclonal antibody, etc.), and radioimmunotherapy (e.g., an anti-CD20 monoclonal antibody conjugated to ^m In, ⁹⁰ Y, or ¹³¹ I, etc.).

[00225] In another embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents, including, but not limited to, radionuclides such as ⁴⁷ Sc, ⁶⁴ Cu, ⁶⁷ Cu, ⁸⁹ Sr, ⁸⁶ Y, ⁸⁷ Y, ⁹⁰ Y, ¹⁰⁵ Rh, ^m Ag, ^m In, ^117m Sn, ¹⁴⁹ Pm, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁷⁷ Lu, ¹⁸⁶ Re, ¹⁸⁸ Re, ²¹¹ At, and ²¹² Bi, optionally conjugated to antibodies directed against tumor antigens.

EXAMPLES

[00226] To provide a more complete understanding of the description provided herein, the following examples are provided. The synthetic examples and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods presented herein and are not to be construed as limiting their scope in any way.

Synthesis Protocols

[00227] The compounds provided herein can be prepared from readily available starting materials using modifications of the specific synthetic protocols set forth below, which are well known to those skilled in the art. It is to be understood that where typical or preferred process conditions (i.e., temperatures, reaction times, molar ratios of reactants, solvents, pressures, etc.) are indicated, other process conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures. A general scheme relating to methods for preparing exemplary compounds of the invention is further described in the section entitled "Methods for Preparing Exemplary Compounds."

[00228] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent undesirable reactions of certain functional groups. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described in Greene et al., Protecting Groups in Organic Synths, Second Edition, Wiley, New York, 1991, and references cited therein.

Abbreviations

[00229] AcOH or HOAc for acetic acid; APCI for atmospheric pressure chemical ionization; 9-BBN for 9-borabicyclo[3.3.1]nonane; BrettPhos for 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl;Precatalyst t-BrettPhos Pd G3 for [(2-di-rubs-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; Precatalyst t-BuBrettPhos Pd G3 for palladium(II) methanesulfonate (2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)); DCM for dichloromethane; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; ESI for electrospray ionization; HPLC for high performance liquid chromatography; i.d. for internal diameter; MS for mass spectrum; NMR for nuclear magnetic resonance; ppm for mass fraction; psi for pounds per square inch; PTFE for polytetrafluoroethylene; RockPhos for 2-di-(rubs-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl; RockPhos Pd G3 Precatalyst for [(2-di-rubs-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate; SFC for supercritical fluid chromatography; TCDI for 1,1'-thiocarbonyldiimidazole; THF for tetrahydrofuran; TLC for thin layer chromatography; v/v for volume/volume; w/v for weight/volume; and w/w for weight/weight.

Example 1: 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 100)

Example 1A: Benzyl 3-(benzyloxy)-7-bromonaphthalene-2-carboxylate

[00230] A mixture of 7-bromo-3-hydroxy-2-naphthoic acid (100 g, 374 mmol) and cesium carbonate (366 g, 1123 mmol) in N,N -dimethylformamide (749 mL) was stirred rapidly for 5 min at 23 °C. Benzyl bromide (89.0 mL, 749 mmol) was then added and the internal temperature was increased to 49 °C. After 90 min, the light yellow mixture was poured into H ₂ O (1.5 L) and the resulting white precipitate was collected by filtration. The collected precipitate was washed successively with _H2O (3×1 L) and tert -butyl methyl ether/heptanes (1:2, 2×300 mL), and then dried under vacuum (15 mbar) at 45°C to constant weight to give the title compound (160.3 g, 358 mmol, 96% yield) as an off-white solid. MS (APCI ⁾ m/z 449 [M+H] ⁺ .

Example 1B: 3-(benzyloxy)-7-bromonaphthalene-2-carboxylic acid

[00231] To a mixture of the product of Example 1A (150.1 g, 336 mmol), water (746 mL), and methanol (1.49 L) was added lithium hydroxide monohydrate (28.2 g, 671 mmol). The thick suspension was stirred with mechanical stirring at the top and heated to an internal temperature of 70 °C. After 3 h, the mixture was cooled to room temperature in an ice bath and 6 M HCl (168 mL) was added over 5 min, causing precipitation of an off-white solid. The solid was collected by filtration and washed with H ₂ O (2 x 1 L), triturated with tert -butyl methyl ether (2 x 300 mL), and dried to constant weight in vacuo at 65 °C to give the title compound (101.5 g, 284 mmol, 85% yield) as a white solid. MS (CIAD ⁺ ) m/z 358 [M+H] ⁺ .

Example 1C. 3-(benzyloxy)-7-bromonaphthalene-2-amine

[00232] To a suspension of the product of Example 1B (101 g, 283 mmol) in toluene (794 mL) and tert -butanol (794 mL) was added triethylamine (41.8 mL, 300 mmol). The cloudy, light yellow solution was heated to an internal temperature of 80 °C under nitrogen, and diphenyl phosphorazidate (64.4 mL, 300 mmol) was added dropwise over 90 min, with the entire reaction under a shield. After 5 h, the reaction mixture was cooled to room temperature, diluted with H ₂ O (1.5 L), and extracted with ethyl acetate (2 x 400 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over sodium sulfate, filtered, and concentrated to give a white solid. The solid was sent for hydrolysis without further purification.

[00233] Diethylenetriamine (253 mL, 2.34 mol) was added to the crude intermediate. The heterogeneous suspension was heated to an internal temperature of 130 °C under nitrogen, forming a homogeneous dark orange solution. After 13 h, the mixture was cooled to room temperature in an ice bath and H ₂ O (800 mL) was slowly added over 3 min, resulting in the precipitation of a yellow solid and an accompanying exotherm to an internal temperature of 53 °C. After cooling the heterogeneous suspension to room temperature, the crude solid was dissolved in CH ₂ Cl ₂ (1.5 L) and the layers were separated. The aqueous layer was re-extracted with CH ₂ Cl ₂ (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over sodium sulfate, filtered, and the volatiles removed in vacuo to give an orange solid. The solid was combined with isopropanol (250 mL) to form a suspension, which was then filtered. The resulting solid was again combined with isopropanol (2 x 100 mL), and the solids were isolated by filtration. The solid was dried in vacuo (13 mbar) at 35 °C to give the title compound (68.48 g, 209 mmol, 74% yield over two steps) as a white solid. MS ( ^APCI ) m/z 329 [M+H] ⁺ .

Example 1D. methyl {[3-(benzyloxy)-7-bromonaphthalen-2-yl]amino}acetate

[00234] To a mixture of the product of Example 1C (67.8 g, 207 mmol) and potassium carbonate (57.1 g, 413 mmol) in N,N -dimethylformamide (354 mL) and H ₂ O (1.861 mL, 103 mmol) was added methyl 2 bromoacetate (29.3 mL, 310 mmol). The suspension was stirred vigorously at room temperature for 5 min, then heated to an internal temperature of 60 °C. After 4 h, the suspension was cooled to room temperature and partitioned between H ₂ O (400 mL) and ethyl acetate (400 mL). The aqueous layer was extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were washed with saturated aqueous ammonium chloride (3 x 60 mL), dried over sodium sulfate, filtered and concentrated to give a pale beige solid. The solid was triturated with heptanes (100 mL) and the resulting beige solid was isolated by filtration, washed with additional heptanes (2 x 30 mL) and dried to constant weight under vacuum (15 mbar) at 35 °C to give the title compound (68.52 g, 171 mmol, 83% yield) as an off-white solid. MS ( ^APCI ) m/z 401 [M+H] ⁺ .

Example 1E: Methyl {[3-(benzyloxy)-7-bromo-1-fluoronaphthalene-2-yl]amino}acetate

[00235] To a solution of the product of Example 1D (15 g, 37.5 mmol) in N,N -dimethylformamide (300 mL) at 2 °C was added a solution of 1-chloromethyl 4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (15.93 g, 45.0 mmol) in N,N -dimethylformamide (100 mL) over 5 min. The resulting solution was stirred for 15 min and then quenched with 0.33 M sodium thiosulfate solution (300 mL, exothermic). The mixture was diluted with ethyl acetate (150 mL) and saturated aqueous ammonium chloride (75 mL) and stirred for 15 min at room temperature. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 75 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4 x 75 mL) and brine (75 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange solid. Ethyl acetate (30 mL) was added to the crude solid and the mixture was sonicated for 30 s. Heptanes (150 mL) were then added slowly via an addition funnel over 15 min. The resulting yellow solid was collected by filtration and washed with 33% v/v ethyl acetate in heptanes (3 x 60 mL). The solid was discarded and the filtrate was concentrated in vacuo to give a yellow-orange solid which was triturated with anhydrous ethanol (45 mL), heated to an internal temperature of 55 °C and stirred for 30 min, then slowly cooled to room temperature. The resulting yellow solid was collected by filtration, then washed with anhydrous ethanol (30 mL) and dried in vacuo (15 mbar) at 50 °C to constant weight to give the title compound (10.1 g, 24.25 mmol, 64.7% yield) as a pale yellow solid. ¹ H NMR (DMSO- d ₆ ) δ ppm. 7.79 (d, J= 2.1 Hz, 1H), 7.65 (dd, J= 8.7, 1.7 Hz, 1H), 7.56-7.51 (m, 2H), 7.46-7.35 (m, 3H), 7.38-7.31 (m, 2H), 7.28 (s, 1H), 5.64 (td, J= 6.7, 2.5 Hz, 1H), 5.28 (s, 2H), 4.21 (dd, J= 6.8, 4.0 Hz, 2H), 3.61 (s, 3H); MS (ESI ⁺ ) m/z 418, 420 [M+H] ⁺ .

Example 1F. methyl {[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl](sulfanoyl)amino}acetate

[00236] To a solution of chlorosulfonyl isocyanate (2.26 mL, 26.0 mmol) in dichloromethane (43.5 mL) at 0 °C was slowly added tert-butanol (2.5 mL, 26.0 mmol) to maintain the internal temperature below 10 °C. After stirring for 30 min at 0 °C, a previously prepared solution of the product of Example 1E (7.25 g, 17.34 mmol) and triethylamine (4.83 mL, 34.7 mmol) in dichloromethane (29.0 mL) was slowly added via an addition funnel to maintain the internal temperature below 10 °C. After complete addition, the addition funnel was rinsed with dichloromethane (12.5 mL). The resulting solution was stirred for 30 min at 0 °C and then allowed to warm to room temperature. After 1 h, the reaction mixture was quenched with H ₂ O (73 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 36 mL). The combined organic layers were washed with 1 M sodium bisulfate (2 x 73 mL). The aqueous washes were re-extracted with dichloromethane (DCM) (36 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an orange foam that was used without purification. MS (APCI ⁺ ) m/z 541, 543 [M- tert -butyl + H] ⁺ .

[00237] To a solution of the crude intermediate in dichloromethane (41 mL) was added trifluoroacetic acid (20 mL, 260 mmol) and the resulting dark solution was stirred at room temperature. After 30 min, the reaction was quenched by slow addition of saturated aqueous sodium bicarbonate (230 mL) via an addition funnel. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were concentrated to give an orange foam, which was suspended in dichloromethane (20 mL) and stirred for 5 min to give a suspension, which was diluted by dropwise addition of heptanes (40 mL) via an addition funnel. The resulting yellow solid was collected by filtration, washed with 25% v/v HCl, and dichloromethane in heptanes (2×20 ml) and dried in vacuo (15 mbar) at 50°C to constant weight to give the title compound (7.5 g, 15.05 mmol, 87% yield). ¹ H NMR (DMSO- d ₆ ) δ ppm. 8.11 (d, J= 2.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.67 (dd, J= 8.8, 2.0 Hz, 1H), 7.58-7.53 (m, 2H), 7.44-7.36 (m, 3H), 7.36-7.30 (m, 1H), 7.07 (s, 2H), 5.26 (s, 2H), 4.47 (d, J= 17.9 Hz, 1H), 4.31 (d, J= 17.8 Hz, 1H), 3.54 (s, 3H); MS (ESI ⁺ ) m/z 497, 499 [M+H] ⁺ .

Example 1G. 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalene-2-yl]-1 λ ^6,2,5 -thiadiazolidine-1,1,3-trione

[00238] To a solution of the product of Example 1F (24.14 g, 48.5 mmol) in tetrahydrofuran (THF) (241 mL) at room temperature was added a solution of sodium methoxide (16.65 mL, 72.8 mmol) (25% w/w in methanol) via syringe, and the resulting solution was stirred at room temperature. After 20 min, the reaction was quenched with 1 M hydrochloric acid (240 mL) and diluted with ethyl acetate (120 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×120 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (120 mL), then dried over sodium sulfate, filtered and concentrated to a total volume of 40 mL to give a dark red solution which was diluted with dichloromethane (75 mL) and concentrated to a total volume of 40 mL. The resulting yellow suspension was diluted with dichloromethane (72 mL) and then slowly diluted with heptanes (72 mL). The suspension was sonicated for 30 s and stirred for 5 min at room temperature. The resulting white solid was collected by filtration then washed with 25% v/v dichloromethane in heptanes (72 mL) and dried under vacuum (15 mbar) at 50 °C to constant weight to give the title compound (16.4 g, 35.2 mmol, 72.5% yield). ¹ H NMR ( _DMSO -d6 ) δ ppm 8.16 (d, J= 2.0 Hz, 1H), 7.87 (dd, J= 8.9, 1.4 Hz, 1H), 7.74 (dd, J= 8.8, 2.0 Hz, 1H), 7.54-7.48 (m, 3H), 7.47-7.29 (m, 3H), 5.28 (s, 2H), 4.54 (s, 2H); MS (IER ^- ) m/z 463, 465 [MH] ^- .

Example 1H. 5-[3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00239] The product of Example 1G (9 g, 19.34 mmol), [(2-di- tert -butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (RockPhos Pd G3 precatalyst, 0.324 g, 0.387 mmol), and cesium carbonate (18.9 g, 58.0 mmol) were combined in a 500 mL round bottom flask. The solids were placed under vacuum and stirred for 5 min, then the flask was flushed with nitrogen and a premix of N,N -dimethylformamide (90 mL) and _H2O (1.045 mL, 58.0 mmol) was added. The resulting suspension was degassed with five additions of vacuum/nitrogen and then heated to an internal temperature of 80°C. After 3 h, the reaction mixture was cooled to room temperature, quenched by the slow addition of 1 M hydrochloric acid (100 mL), and diluted with ethyl acetate (100 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 saturated aqueous ammonium chloride (4 x 50 mL). The combined aqueous washes were back-extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (50 mL), then dried over sodium sulfate, filtered, and concentrated to give a viscous dark oil. The crude oil was dissolved in acetonitrile (9 mL), then tert- butyl methyl ether (180 mL) was added via dropping funnel over 5 min with vigorous stirring. The resulting black solid was removed by filtration and washed with 50% v/v tert-butyl methyl ether in ethyl acetate (2 x 45 mL). The solid was discarded and the filtrate was concentrated in vacuo. The resulting dark oil was diluted with methanol (9 mL), then ammonia in methanol (2.76 mL, 7 M, 19.34 mmol) was added. The resulting solution was diluted by slowly adding 50% v/v ethyl acetate in heptanes (135 mL) via dropping funnel. The resulting solid was collected by filtration, then washed with cold filtrate, then 50% v/v tert-butyl methyl ether in ethyl acetate (2 x 45 mL). ethyl acetate in heptanes (45 ml) and dried in vacuo (15 mbar) at 50°C to constant weight to give the title compound as an ammonium salt (6.33 g, 15.10 mmol, 78% yield). ¹ H NMR (DMSO- d ₆ ) δ ppm. 9.81 (s, 1H), 7.68 (dd, J= 8.9, 1.4 Hz, 1H), 7.60-7.49 (m, 2H), 7.39-7.31 (m, 2H), 7.33-7.26 (m, 1H), 7.23 (s, 1H), 7.14 (d, J= 2.5 Hz, 1H), 7.10 (dd, J= 8.8, 2.5 Hz, 1H), 5.19 (s, 2H), 4.08 (s, 2H); MS (IER ^- ) m/z 401 [MH] ^- .

Example 1I. 5-[3-(benzyloxy)-1-fluoro-7-(3-methylbutoxy)naphthalene-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00240] A mixture of Example 1H (300 mg, 0.746 mmol), cesium carbonate (486 mg, 1.491 mmol) and 1-bromo-3-methylbutane (169 mg, 1.18 mmol) in N,N -dimethylformamide (DMF) (2 mL) was stirred at room temperature for 14 h. To the reaction mixture were added _{2N Na2CO3} (0.7 mL) and ethyl acetate (10 mL) to give a suspension. The solid was collected by filtration to give the title compound (260 mg, yield 74%). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 7.74 (dd, J= 9.1, 1.5 Hz, 1H), 7.59-7.52 (m, 2H), 7.41-7.22 (m, 5H), 7.19 (dd, J= 9.0, 2.5 Hz, 1H), 5.22 (s, 2H), 4.12 (t, J= 6.7 Hz, 2H), 4.08 (s, 2H), 1.83 (dp, J= 13.3, 6.6 Hz, 1H), 1.68 (k, J= 6.6 Hz, 2H), 0.96 (d, J= 6.6 Hz, 6H); MS (CIBP ^- ) m/z 471.4 [MH] ^- .

Example 1J: 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00241] To a solution of Example 1I (140 mg, 0.296 mmol) in 2,2,2-trifluoroethanol (1.5 mL) was added 10% Pd/C (144 mg, 1.353 mmol) in a 20 mL Parr® Barnstead Hastelloy C reactor and the mixture was stirred at 35 °C under 140 psi hydrogen pressure for 40 h. An additional 10% Pd/C (140 mg, 1.316 mmol) was added while continuing hydrogenation at 35 °C under 140 psi hydrogen pressure for 90 h. The reaction mixture was filtered, concentrated and purified by preparative HPLC on a Phenomenex® C8(2) Luna® 5 μm AXIA™ 150×30 mm column eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/min (0-0.5 min 5% A, 0.5-8.5 min linear gradient 05-100% A, 8.7-10.7 min 100% A, 10.7-11 min linear gradient 100-05% A) to afford the title compound with an impurity. The title compound was further purified by preparative HPLC on a Phenomenex® C8 (2) Luna® 5 μm AXIA™ 150 x 30 mm column eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/min (0-0.5 min 5% A, 0.5-20.5 min linear gradient 05-100% A, 20.7-22.7 min 100% A, 22.7-23 min linear gradient 100-05% A) to afford the title compound (12 mg, 0.031 mmol, 10.5% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 10.00 (s, 1H), 6.47 (s, 1H), 4.35 (s, 2H), 3.70 (m, 1H), 3.48 (m, 2H), 2.82 (dd, J= 16.4, 4.9 Hz, 1H), 2.74 (m, 1H), 2.68-2.58 (m, 1H), 2.50-2.43 (m, 1H), 1.90-1.81 (m, 1H), 1.79-1.70 (m, 1H), 1.64 (m, 1H), 1.38 (k, J= 6.8 Hz, 2H), 0.86 (dd, J= 6.7, 2.1 Hz, 6H); MS (CIAD ^- ) m/z 385.3 [MH] ^- .

Example 2: 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 101)

Example 2A: 5-{3-(benzyloxy)-7-[(2-cyclopropylethyl)amino]-1-fluoronaphthalene-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00242] In a 20 mL pressure release vial, the product from Example 1G (0.500 g, 1.075 mmol), cesium carbonate (1.050 g, 3.22 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3 precatalyst, 0.029 g, 0.032 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 0.017 g, 0.032 mmol) were combined and The reaction mixture was placed under vacuum for 5 min. The vessel was then flushed with nitrogen and tert-amyl alcohol (10 mL) was added, followed by 2-cyclopropylethylamine (0.203 mL, 2.15 mmol). The mixture was placed under vacuum followed by nitrogen flushes for 5 cycles, stirred for 10 min (became a suspension), and then heated to 90 °C. After 24 h, the reaction mixture was cooled to room temperature and then quenched with 1 M hydrochloric acid (8 mL). The aqueous layer was extracted with ethyl acetate (3 x 5 mL), and the combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid. The organic fraction was then dried over sodium sulfate, filtered, and concentrated in vacuo. The crude oil was dissolved in acetonitrile and concentrated (2 x 5 mL) to give the title compound, which was used without purification in the next step. MS (CIBP ^- ) m/z 468 [MH] ^- .

Example 2B: 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00243] To a suspension of the product from Example 2A (2.15 mmol) and pentamethylbenzene (0.637 g, 4.30 mmol) in dichloromethane (20 mL) at an internal temperature of -78 °C was added a solution of boron trichloride (12.9 mL, 12.89 mmol, 1 M in dichloromethane) slowly along the wall of the flask to maintain the internal temperature below -65 °C. After 5 min, the cooling bath was removed and the solution was allowed to warm. When the internal temperature reached 0 °C, the reaction mixture was recooled to -78 °C and quenched with ethyl acetate (5 mL) and then ethanol (5 mL). The mixture was warmed to room temperature and then concentrated in vacuo to give a solid. The solid was triturated with heptanes (3 x 10 mL), 1:1 heptanes/ethyl acetate (2 x 5 mL), and acetonitrile (2 x 3 mL) to give the title compound as a solid (0.654 g, 1.73 mmol, 80% yield). ¹ H NMR (DMSO- d ₆ ) δ ppm. 7.45 (dd, J = 8.9, 1.6 Hz, 1H), 6.97 (dd, J= 8.9, 2.3 Hz, 1H), 6.88 (d, J= 1.4 Hz, 1H), 6.61 (d, J= 2.2 Hz, 1H), 5.82 (t, J= 5.5 Hz, 1H), 4.07 (s, 2H), 3.14 (tdd, J = 7.0, 4.2 Hz, 2H), 1.51 (k, J= 7.0 Hz, 2H), 0.84 (tdd, J= 10.2, 7.5, 3.8 Hz, 1H), 0.50-0.37 (m, 2H), 0.14-0.06 (m, 2H); MS (IER ^- ) m/z 378 [MH] ^- .

Example 2C.2: 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ 6,2,5-thiadiazolidine-1,1,3-trione

[00244] In a Parr shaker, 10% palladium on carbon (0.443 g, 0.416 mmol) as a solid was added to a solution of the product from Example 2B (0.654 g, 1.725 mmol) in a mixture of acetic acid (6 mL) and methanol (3 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (2 weeks). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. The filtrate was then concentrated in vacuo to give a brown solid which was purified by preparative reverse phase HPLC, OBD Waters XBridge™ C18 5 μm, 30×100 mm column, flow rate 40 mL/min, gradient 5-60% _CH3OH in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to ₁₀ with ammonium hydroxide) at 210 nm to give the title compound (0.114 g, 0.297 mmol, 14% yield). ¹ H NMR (501 MHz, DMSO -d6 ) δ ppm. 9.28 (s, 1H), 8.43 (s, 2H), 6.47 (s, 1H), 3.94 (d, J= 1.6 Hz, 2H), 3.17 (d, J= 3.0 Hz, 1H), 3.13-3.05 (m, 3H), 2.81 (dt, J= 17.3, 4.7 Hz, 1H), 2.73 (ddd, J= 17.1, 11.1, 5.3 Hz, 1H), 2.57-2.47 (m, 1H), 2.17 (dt, J= 12.9, 4.1 Hz, 1H), 1.68 (cd, J= 11.6, 5.5 Hz, 1H), 1.52 (k, J= 7.2 Hz, 2H), 0.76 (ddd, J= 12.5, 8.0, 4.9 Hz, 1H), 0.50-0.41 (m, 2H), 0.13 (q, J= 4.9 Hz, 2H); MS (ESI ^- ) m/z 382 [MH] ^- .

Example 3: 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 102)

Example 3A: 5-{3-(benzyloxy)-1-fluoro-7-[(3-methylbutyl)amino]naphthalene-2-yl} ^-1λ6,2,5 -thiadiazolidine-1,1,3-trione

[00245] In a 20 mL pressure release vial, the product from Example 1G (0.500 g, 1.075 mmol), cesium carbonate (1.050 g, 3.22 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3 precatalyst, 0.029 g, 0.032 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 0.017 g, 0.032 mmol) were combined and The reaction mixture was placed under vacuum for 5 min. The vessel was flushed with nitrogen and tert -amyl alcohol (10 mL) was added followed by isoamylamine (0.25 mL, 2.149 mmol). The reaction mixture was degassed with 5 cycles of vacuum and nitrogen blanketing, stirred for 10 min and then heated to 90 °C. After 24 h, the reaction mixture was cooled to room temperature and then quenched with 1 M hydrochloric acid (8 mL). The aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in acetonitrile and concentrated (2 x 5 mL) to give the title compound, which was used without purification in the next step. MS (HIBP ^- ) m/z 470 [MH] ^- .

Example 3B: 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00246] To a suspension of the product from Example 3A (2.149 mmol) and pentamethylbenzene (0.637 g, 4.30 mmol) in dichloromethane (20 mL) at an internal temperature of -78 °C was added a solution of boron trichloride (12.9 mL, 12.9 mmol, 1 M in dichloromethane) slowly along the wall of the flask to maintain the internal temperature below -65 °C. After 5 min, the cooling bath was removed and the solution was allowed to warm. When the internal temperature reached 0 °C, the reaction mixture was recooled to -78 °C and quenched with ethyl acetate (5 mL) and then ethanol (5 mL). The mixture was warmed to room temperature and then concentrated in vacuo. The solid was triturated with heptanes (3 x 10 mL), then 1:1 heptanes/ethyl acetate (2 x 5 mL) and acetonitrile (2 x 3 mL) to give the title compound (0.475 g, 1.25 mmol, 58% yield). ¹ H NMR (DMSO- d ₆ ) δ ppm. 9.86 (s, 1H), 7.53 (d, J= 8.9 Hz, 1H), 7.08 (dd, J= 8.9, 2.3 Hz, 1H), 6.94 (s, 1H), 6.78 (s, 1H), 4.39 (s, 2H), 3.16-3.07 (m, 2H), 172 (dk, J= 13.3, 6.7 Hz, 1H), 1.51 (k, J= 7.1 Hz, 2H), 0.93 (d, J= 6.7 Hz, 6H); MS (IER ^- ) m/z 380 [MH] ^- .

Example 3C: 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00247] In a Parr shaker, 10% palladium on carbon (0.458 g, 0.430 mmol) was added to a solution of the product from Example 3B (0.4572 g, 1.199 mmol) in acetic acid (5 mL), the reactor was purged with nitrogen, and then stirred under 120 psi of hydrogen gas at 25°C until all hydrogen was consumed (2 weeks). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. The filtrate was then concentrated in vacuo and the residue was purified by preparative reverse phase HPLC, Waters XBridge™ C18, 5 µm OBD, 30 x 100 mm, flow rate 40 mL/min, gradient 5-60% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide), monitoring at 210 nm to give the title compound (0.143 g, 0.371 mmol, 31% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm. 9.22 (s, 1H), 8.39 (lat s, 2H), 6.47 (s, 1H), 3.93 (s, 2H), 3.43-3.35 (m, 1H), 3.09 (dd, J= 16.0, 5.6 Hz, 1H), 3.03 (td, J= 7.0, 2.1 Hz, 2H), 2.81 (dt, J= 17.2, 4.7 Hz, 1H), 2.73 (ddd, J= 17.0, 11.0, 5.3 Hz, 1H), 2.56-2.51 (m, 1H), 2.20-2.13 (m, 1H), 1.68 (ddt, J= 17.2, 13.1, 6.0 Hz, 2H), 1.50 (dt, J= 9.7, 6.8 Hz, 2H), 0.92 (d, J - 6.6 Hz, 6H); MS (ESI ^- ) m/z 384 [MH] ^- .

Example 4: 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 103)

Example 4A: 5-{3-(benzyloxy)-7-[(cyclopropylmethyl)amino]-1-fluoronaphthalene-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00248] In a 20 mL pressure release vial, the product from Example 1G (0.50 g, 1.08 mmol), cesium carbonate (1.05 g, 3.22 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3 precatalyst, 0.029 g, 0.032 mmol), and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 0.017 g, 0.032 mmol) were combined and placed under vacuum for 5 min. The vessel was then flushed with nitrogen and tert -amyl alcohol (10 mL) was added, followed by cyclopropylmethylamine (0.19 mL, 2.15 mmol). The mixture was degassed with 5 cycles of vacuum and nitrogen blanketing, stirred for 10 min, and then heated to 90 °C. After 7 h, the reaction mixture was cooled to room temperature and then quenched with 1 M hydrochloric acid (8 mL). The aqueous layer was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid, then dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was dissolved in acetonitrile and concentrated (2 x 5 mL) to give the title compound, which was used without purification in the next step. MS (APCI ^- ) m / z 454 [MH] ^- .

Example 4B: 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00249] To a suspension of the product from Example 4A (1.075 mmol) in dichloromethane (10 mL) at an internal temperature of -78 °C was slowly added a solution of boron trichloride (6.45 mL, 6.45 mmol, 1 M in dichloromethane) along the wall of the flask to maintain the internal temperature below -65 °C. After 5 min, the cooling bath was removed and the solution was allowed to warm. When the internal temperature reached 0 °C, the reaction mixture was recooled to -78 °C and quenched with ethyl acetate (5 mL) and then ethanol (5 mL). The mixture was warmed to room temperature and then concentrated in vacuo. The residue was triturated with heptanes (3 x 5 mL), then 1:1 heptanes/ethyl acetate (2 x 3 mL) and acetonitrile (2 x 3 mL) to give the title compound (0.129 g, 0.353 mmol, 33% yield). ¹ H NMR (DMSO- d ₆ ) δ ppm. 10.06 (s, 1H), 7.60 (d, J= 8.9 Hz, 1H), 7.19 (dd, J= 8.9, 2.3 Hz, 1H), 6.97 (d, J = 4.8 Hz, 2H), 4.42 (s, 2H), 3.05 (d, J= 6.8 Hz, 2H), 1.13-1.03 (m, 1H), 0.57-0.47 (m, 2H), 0.31-0.25 (m, 2H); MS (ESI ^- ) m/z 364 [MH] ^- .

Example 4C. 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00250] In a Parr shaker, 10% palladium on carbon (0.122 g, 0.115 mmol) was added to a solution of the product from Example 4B (0.068 g, 0.187 mmol) in acetic acid (2 mL). The reactor was purged with nitrogen and then stirred under 120 psi of hydrogen gas at 25°C until all hydrogen was consumed (2 weeks). The reactor was purged with nitrogen, the crude reaction mixture was filtered, and the solid was washed with methanol. The filtrate was then concentrated in vacuo and the residue was purified by preparative reverse phase HPLC, OBD Waters XBridge™ C18 5 μm, 30×100 mm column, flow rate 40 mL/min, gradient 5-30% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide) at 205 nm to give the title compound as the ammonium salt (0.0046 g, 0.012 mmol, 6% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm. 9.07 (s, 1H), 6.42 (s, 1H), 3.92 (d, J= 1.6 Hz, 2H), 3.07-3.00 (m, 1H), 2.78-2.71 (m, 1H), 2.69-2.60 (m, 2H), 2.37-2.28 (m, 1H), 2.01-1.95 (m, 1H), 1.86-1.80 (m, 1H), 1.67-1.61 (m, 1H), 1.56-1.49 (m 1H), 0.87-0.80 (m, 1H), 0.49-0.44 (m, 2H), 0.23-0.18 (m, 2H); MS (IER ^- ) m/z 368 [MH] ^- .

Example 5: 5-[(7 R )-1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 104)

Example 5A: Benzyl 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylate

[00251] A mixture of 3-hydroxy-7-methoxy-2-naphthoic acid (75 g, 344 mmol) and cesium carbonate (336 g, 1031 mmol) in N,N -dimethylformamide (687 mL) was stirred rapidly for 5 min at 23 °C. Benzyl bromide (84 mL, 705 mmol) was then added. After 90 min, the mixture was poured into H ₂ O (1 L) and extracted with ethyl acetate (4 x 300 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3 x 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown solid. The crude solid was collected by filtration, suspended in tert -butyl methyl ether:heptanes (1:2, 3×100 mL), then dried under vacuum (12 mbar) at 40°C to give the title compound (122.5 g, 307 mmol, 89% yield) as a beige solid. MS ( ^APCI ) m/z 399 [M+H] ⁺ .

Example 5B: 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylic acid

[00252] To a suspension of the product of Example 5A (122.5 g, 307 mmol) in methanol (780 mL) was added 6 M aqueous sodium hydroxide (154 mL, 922 mmol). The heterogeneous brown suspension was stirred with an overhead mechanical stirrer and heated to an internal temperature of 68 °C. After 15 min, the mixture was cooled to room temperature in an ice bath and 6 M HCl (250 mL) was added over 5 min. The off-white solid was collected by filtration, washed with H ₂ O (3 x 500 mL), and dried to constant weight in vacuo at 65 °C to give the title compound (84.1 g, 273 mmol, 89% yield) as a white solid. MS (APCI ⁺ ) m/z 309 [M+H] ⁺ .

Example 5C. 3-(benzyloxy)-7-methoxynaphthalene-2-amine

[00253] To a suspension of the product of Example 5B (84.1 g, 273 mmol) in toluene (766 mL) and tert-butanol (766 mL) was added triethylamine (40.3 mL, 289 mmol). The homogeneous black solution was heated to an internal temperature of 80 °C under nitrogen, and diphenyl phosphorazidate (62.2 mL, 289 mmol) was added dropwise over 90 min, with the entire reaction under a shield. After 5 h, the reaction mixture was cooled to room temperature, diluted with H ₂ O (1.5 L), and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated to give 180.1 g of a dark brown solid. The solid substance was sent for hydrolysis without further purification.

[00254] Diethylenetriamine (475 mL, 4.40 mol) was added to the crude intermediate. The heterogeneous suspension was heated to an internal temperature of 130 °C under nitrogen, forming a homogeneous dark orange solution. After 16 h, the mixture was cooled to room temperature in an ice bath and H ₂ O (1.5 mL) was slowly added over 3 min, resulting in the precipitation of a yellow solid and an accompanying exotherm to an internal temperature of 62 °C. After cooling the heterogeneous suspension to room temperature, the crude solid was dissolved in CH ₂ Cl ₂ (1.5 L) and the layers were separated. The aqueous layer was re-extracted _{with CH2Cl2} (3×150 mL) and the combined organic layers were washed with brine (3×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 78.8 g of an orange solid. The solid was suspended with isopropanol (50 mL), collected by filtration, re-slurried with isopropanol (1×50 mL) and dried in vacuo (15 mbar) at 35 °C to give the title compound (60.12 g, 215 mmol, 79% yield over two steps) as a yellow solid. MS (APCI ⁾ m/z 280 [M+H] ⁺ .

Example 5D. methyl {[3-(benzyloxy)-7-methoxynaphthalene-2-yl]amino}acetate

[00255] To a mixture of the product of Example 5C (59.2 g, 212 mmol) and potassium carbonate (58.6 g, 424 mmol) in N,N -dimethylformamide (363 mL) and H ₂ O (1.91 mL, 106 mmol) was added methyl 2-bromoacetate (30.1 mL, 318 mmol). The suspension was stirred vigorously at room temperature for 5 min and then heated to an internal temperature of 60 °C. After 70 min, the suspension was cooled to room temperature and diluted with H ₂ O (600 mL) and ethyl acetate (500 mL). The aqueous layer was extracted with ethyl acetate (2 x 300 mL) and the combined organic layers were washed with saturated aqueous ammonium chloride (3 x 60 mL), dried over sodium sulfate, filtered and concentrated to give 104.3 g of a pale yellow beige solid. The solid was triturated with heptanes (200 mL). The resulting beige solid was collected by filtration, washed with additional heptanes (2 x 30 mL) and dried under vacuum (15 mbar) at 35 °C to give the title compound (72.27 g, 206 mmol, 97% yield) as an off-white solid. MS ( ^APCI ) m/z 352 [M+H] ⁺ .

Example 5E. methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalene-2-yl]amino}acetate

[00256] Tetrahydrofuran (THF) (854 mL) was added to a mixture of the product of Example 5D (30.0 g, 85 mmol) and N -fluorobenzenesulfonimide (26.9 g, 85 mmol), and the resulting homogeneous yellow solution was stirred at room temperature. After 90 min, residual oxidizing agent was quenched by adding a solution of sodium thiosulfate pentahydrate (10.59 g, 42.7 mmol) in water (150 mL), and the mixture was stirred at room temperature for 30 min. Ethyl acetate (600 mL) was then added, the aqueous layer was separated, and the organic layer was washed with a solution of sodium carbonate (18.10 g, 171 mmol) in water (30 mL) and then with water:brine (1:1, 1×20 mL). The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo to give a bright yellow/orange solid. The solids were triturated with tert-butyl methyl ether (300 mL), collected by filtration, and the filter cake ( N- (phenylsulfonyl)benzenesulfonamide) was washed with tert -butyl methyl ether (2 x 100 mL). The filtrate was concentrated to give 34.6 g of a dark red oil which was purified by flash chromatography (750 g SiO ₂ , heptanes to 20% ethyl acetate/heptanes) to give the title compound (16.07 g, 43.5 mmol, 51% yield) as a yellow solid. MS ( ^APCI ) m/z 370 [M+H] ⁺ .

Example 5F. methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalene-2-yl](sulfamoyl)amino}acetate

[00257] To a solution of chlorosulfonyl isocyanate (5.13 mL, 59.1 mmol) in dichloromethane (83 mL) at 0 °C was slowly added tert -butanol (5.65 mL, 59.1 mmol) such that the internal temperature remained below 10 °C. After stirring for 30 min at 0 °C, a previously prepared solution of the product of Example 5E (14.55 g, 39.4 mmol) and triethylamine (10.98 mL, 79 mmol) in dichloromethane (68.9 mL) was slowly added via an addition funnel such that the internal temperature remained below 10 °C. After complete addition, the addition funnel was rinsed with dichloromethane (23 mL). The resulting solution was stirred for 30 min at 0 °C, and then the reaction mixture was quenched with H ₂ O (20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange oil. The residue was dissolved in ethyl acetate (200 mL) and washed with water:brine (1:1, 2 x 50 mL) to remove residual triethylamine hydrochloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl][( tert -butoxycarbonyl)sulfamoyl]amino}acetate, which was used without purification.

[00258] To a solution of methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl][(tert-butoxycarbonyl)sulfamoyl]amino}acetate in dichloromethane (98 mL) was added trifluoroacetic acid (45.5 mL, 591 mmol), and the resulting dark solution was stirred at room temperature. After 20 min, the reaction was quenched by the slow addition of saturated aqueous sodium bicarbonate (691 mL) via an addition funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were concentrated to give a dark red oil; On addition of tert -butyl methyl ether (60 mL), a yellow solid precipitated which was collected by filtration, washed with tert-butyl methyl ether (2 x 30 mL) and dried under vacuum (15 mbar) at 35 °C to give the title compound (13.23 g, 29.5 mmol, 75% yield over two steps) as a light yellow solid. MS (ESI ⁺ ) m/z 449 [M+H] ⁺ .

Example 5G. 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00259] To a solution of the product of Example 5F (13.23 g, 29.5 mmol) in tetrahydrofuran (THF) (355 mL) at room temperature was added solid potassium tert -butoxide (3.31 g, 29.5 mmol), and the resulting solution was stirred at room temperature. After 10 min, the reaction was quenched with 1 M hydrochloric acid (90 mL) and diluted with ethyl acetate (400 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 120 mL). The combined organic layers were washed with brine (3 x 50 mL), then dried over sodium sulfate, filtered, and concentrated. The crude 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione was used in the subsequent reaction without further purification.

[00260] A mixture of the crude intermediate, 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (12.28 g, 29.5 mmol) and pentamethylbenzene (13.11 g, 88 mmol) in dichloromethane (147 mL) was cooled to an internal temperature of -76 °C under dry nitrogen. Then, 1 M boron trichloride solution (59.0 mL, 59.0 mmol) in CH ₂ Cl ₂ was added dropwise over 15 min to keep the internal temperature below -72 °C. During the addition, the reaction turned dark brown and became homogeneous. Incomplete conversion was observed and additional boron trichloride (2 x 5.90 mL, 2 x 5.90 mmol) was added resulting in complete conversion. The reaction was quenched at -75 °C _{with CH2Cl2} :methanol (10:1, 140 mL) via cannula transfer under nitrogen for 15 min, then slowly warmed to room temperature over 20 min under nitrogen. The volatiles were removed in vacuo to give a brown/oak bark solid which was collected by filtration and suspended with heptanes (5 x 40 mL) and _CH2Cl2 (3 x 40 mL). The crude solid was suspended in isopropanol (75 mL), heated until the material dissolved, then allowed to cool slowly to room temperature over 1 _h . The solid was collected by filtration, washed with heptanes (2 x 30 mL) and dried under vacuum (15 mbar) at 60 °C to give 5.11 g of a white solid. The mother liquor was concentrated and the process was repeated to give an additional 1.96 g of a white solid. The batches were combined to give the title compound (7.07 g, 21.67 mmol, 73.5% yield over two steps). ¹ H NMR (methanol- d ₄ ) δ ppm. 7.60 (dd, J = 9.1, 1.5 Hz, 1H), 7.25 (d, J= 2.6, 1H), 7.16 (dd, J= 9.1, 2.6 Hz, 1H), 7.04 (s, 1 H), 4.56 (s, 2H), 3.89 (s, 3 H); MS (IER ^- ) m/z 325 [MH] ^- .

Example 5H. 5-{3-[(benzyloxy)methoxy]-1-fluoro-7-methoxy-5,6,7,8-tetrahydronaphthalene-2-yl}-2-[(benzyloxy)methyl]-1 λ ^6,2 , 5-thiadiazolidine-1,1,3-trione

[00261] A solution of the intermediate compound of Example 5G (785 mg, 1.89 mmol) in acetic acid (10 mL) was added to 10% Pd/C, dry (800 mg). The mixture was stirred for 46 h under 200 psi of hydrogen pressure and 25 °C. After filtration, the filtrate was concentrated to a minimum volume. Toluene (5 mL) was added, the mixture was concentrated to a minimum volume, and this was repeated a second time to remove residual acetic acid. The resulting solid was dried in a vacuum oven at 50°C to give the crude product as 5-(1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione containing a significant amount of des-OCH ₃ by-product. This mixture was used without purification in the next step. MS (ESI ^- ) m/z 329 [MH] ^- .

[00262] A solution of crude 5-(1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione from the previous step and dichloromethane (6.2 mL) was stirred at ambient temperature and N,N -diisopropylethylamine (0.988 mL, 5.66 mmol) was added. Benzyl chloromethyl ether (0.655 mL, 4.71 mmol) was added dropwise and stirring was continued at ambient temperature. After 1 h, the reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous NaHCO ₃ (10 mL) and brine (2 mL), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography (40 g SiO ₂ , heptanes to 50% tert -butyl methyl ether/heptanes, gradient elution) to give the title compound (318 mg, 0.557 mmol, 30% yield over two steps). ¹ H NMR (501 MHz, DMSO -d ₆ ) δ ppm. 7.38-7.21 (m, 10H), 6.88 (s, 1H), 5.31 (s, 2H), 5.21 (s, 2H), 4.65 (s, 2H), 4.62 (s, 2H), 4.61 (s, 2H), 3.69 (dtd, J= 7.5, 5.0, 2.6 Hz, 1H), 3.29 (s, 3H), 2.89-2.77 (m, 2H), 2.71 (dt, J= 17.3, 6.2 Hz, 1H), 2.61 (dd, J= 16.8, 5.8 Hz, 1H), 1.92-1.78 (m, 2H); MS (CIAD ⁺ ) m/z 588 [M+H ₂ O] ⁺ .

Example 5I. 5-{(7R)-3-[(benzyloxy)methoxy]-1-fluoro-7-methoxy-5,6,7,8-tetrahydronaphthalene-2-yl}-2-[(benzyloxy)methyl]-1 λ ^6,2,5 -thiadiazolidine-1,1,3-trione

[00263] The racemic material from Example 5H was purified by preparative SFC performed on a Waters SFC 80Q system running ChromScope™ software. The preparative SFC system was equipped with a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 supplied by a dry non-certified _CO2 dewar at 350 psi with methanol modifier at a flow rate of 80 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 120 bar. Sample was loaded into the modifier stream in 1 mL (50 mg) injections. The mobile phase was maintained isocratically at 30% cosolvent: _CO2 . Fraction collection was thresholded. The instrument was equipped with a Diacel CHIRALPAK® 30 cm column with 30 mm i.d. x 250 mm 5 μm particles. Early eluted fractions containing the desired product were pooled and concentrated to give the title compound (97 mg, 0.17 mmol, 31% yield). Late eluted fractions containing the opposite enantiomer were concentrated and used in Example 10. Characterization was identical to the product from Example 5H and absolute stereochemistry was assigned arbitrarily.

Example 5J: 5-[(7R)-1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00264] A solution of the product of Example 5I (94 mg, 0.17 mmol) in tetrahydrofuran (2 mL) was added to 20% Pd(OH) ₂ /C, wet (190 mg), and the mixture was stirred under 60 psi of hydrogen pressure and 25°C for 18 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 AXIA™ (30 mm × 225 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A). Samples were injected into 1.5 mL of dimethyl sulfoxide:methanol (1:1). A custom cleanup system was used consisting of the following modules: Waters LC4000 preparative pump; Waters 996 diode array detector; Waters 717+ autosampler; Waters SAT/IN module, Alltech Varex III evaporative light scattering detector; Gilson 506C interface unit. and two Gilson FC204 fraction collectors. The system was controlled by Waters Millennium32 software, automated by a Visual Basic application developed by Abbott for fraction collector control and fraction tracking. Fractions were collected based on a UV signal threshold, and selected fractions were then analyzed by flow injection mass spectrometry using positive APCI ionization on a Finnigan Navigator using 70:30 methanol:10 mM _NH4OH (aqueous) at a flow rate of 0.8 mL/min. Loop injection mass spectra were acquired using a Finnigan Navigator running Navigator 1.8 software and a Gilson 215 liquid handler for fraction injection controlled by a Visual Basic application developed by Abbott. The product-containing fractions were pooled and lyophilized to give Example 5J (34 mg, 0.10 mmol, 63% yield). The characteristics were identical to the final product of Example 11, and the absolute stereochemistry was assigned arbitrarily.

Example 6: 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 105)

Example 6A: 5-(7-bromo-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00265] A dry 250 mL round bottom flask was charged with the product from Example 1G (4 g, 8.60 mmol) and 1,2,3,4,5-pentamethylbenzene (2.55 g, 17.2 mmol). The flask was purged with dry nitrogen for 5 min and then charged _{with CH2Cl2} (80 mL). The cloudy white suspension was cooled to -78 °C and _a 1 M solution of trichloroborane (25.8 mL, 25.8 mmol) in _CH2Cl2 was added dropwise over 15 min. The reaction mixture was allowed to stir for 30 min after the addition was complete and then quenched at -78 °C with ethyl acetate (30 mL) followed by the rapid addition of methanol (5.22 mL). The mixture was then slowly warmed to ambient temperature over 20 min under nitrogen. The volatiles were removed under reduced pressure to give an off-white solid. The solid was suspended in ethyl acetate/heptanes (1:1, 30 mL), stirred for 5 min, and then isolated by filtration. The resulting solid was suspended with additional ethyl acetate:heptanes (1:1, 2 x 5 mL), then heptanes (2 x 5 mL), and again isolated by filtration. The resulting solids were dried to constant weight to give the title compound (2.9 g, 7.73 mmol, 90% yield) as a white solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm. 10.89 (s, 1H), 8.09 (d, J= 2.0 Hz, 1H), 7.78 (dd, J= 9.0, 1.3 Hz, 1H), 7.64 (dd, J= 8.8, 2.0 Hz, 1H), 7.15 (s, 1H), 4.50 (s, 2H).

Example 6B: 5-{7-[(E)-2-cyclopropylethenyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00266] To a solution of the product of Example 6A (0.134 g, 0.36 mmol) was added dioxane:water (3:1, 3.6 mL, 0.1 M), followed by ( E )-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.139 g, 0.714 mmol) and potassium carbonate (0.148 g, 1.072 mmol). _N2 was bubbled into this suspension for 10 min, followed by the addition of 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride. Sparging was continued for 5 min, and then the biphasic suspension was heated at 80 °C for 12 h. The mixture was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. The resulting residue was purified over _SiO2 (0-25% methanol in ethyl acetate) to give the title compound (0.048 g, 0.132 mmol, 37%). MS (ESI ^- ) m/z 361 [MH] ^- .

Example 6C. 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00267] The product of Example 6B (0.048 g, 0.132 mmol) and trifluoroethanol (2 mL) were added to 10% Pd/C, dry (0.014 g, 0.132 mmol) in a 20 mL Parr® Barnstead Hastelloy C reactor. The mixture was allowed to stir for 86 h under hydrogen atmosphere (158 psi) at 25°C. The reaction mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by reversed-phase HPLC (Phenomenex® C8(2) Luna® 5 µm AXIA™ 150×30 mm, acetonitrile in water (containing 0.1% trifluoroacetic acid) from 3% to 100% gradient over 18 minutes (3 mL/min to 100 mL/min) to give the title compound (0.013 g, 27%).¹H NMR (400 MHz, DMSO-d ₆)δm.d. 6.37 (s, 1H), 3.89 (s, 2H), 2.76-2.55 (m, 3H), 2.06-1.95 (m, 1H), 1.83-1. 75 (m, 1H), 1.66-1.47 (m, 1H), 1.39 (k, J=7.0 Hz, 2H), 1.30-1.18 (m, 3H), 0.64 (pd,J=7.3, 3.7 Hz, 1H), 0.40-0.30 (m, 2H), -0.07 (d, J=4.5 Hz, 2H); MS (IER)^-)m/z367 [M-H]^-.

Example 7: 5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 106)

Example 7A: 5-[3-(benzyloxy)-1-fluoro-7-(2-methoxyethoxy)naphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00268] A mixture of the product of Example 1H (97 mg, 0.24 mmol), 1-bromo-2-methoxyethane (66.7 mg, 0.480 mmol) and cesium carbonate (180 mg, 0.552 mmol) in N,N -dimethylformamide (0.8 mL) was stirred at 75 °C for 40 min. The solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane then dichloromethane:methanol (10:1) to give the title compound (100 mg, 0.217 mmol, 90% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.76 (d, J= 8 Hz, 1H), 7.56 (d, J= 8 Hz, 2H), 7.37 (t, J= 8 Hz, 2H), 7.32 (m, 1H), 7.30 (lat s, 1H), 7.25 (d, J= 2 Hz, 1H), 7.21 (dd, J= 8, 2 Hz, 1H), 5.21 (s, 2H), 4.21 (m, 2H), 4.08 (s, 2H), 3.72 (m, 2H), 3.33 (s, 3H); MS (IER ^- ) m/z 459 [MH] ^- .

Example 7B: 5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00269] A solution of Example 7A (320 mg, 0.695 mmol) in acetic acid (4 mL) was placed in a 20 mL Parr® Barnstead Hastelloy C reactor. 10% Pd/C (320 mg, 3.01 mmol) was added and the mixture was stirred at 25 °C under 140 psi hydrogen for 15 h. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC on a Phenomenex® C8(2) Luna® 5 μm AXIA™ 150×30 mm column eluting with acetonitrile (A) and 10 mM ammonium acetate in water (B) at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to afford the title compound (30 mg 0.080 mmol, 11.53% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.42 (d, J= 1.4 Hz, 1H), 3.93 (s, 2H), 3.79-3.69 (m, 1H), 3.66-3.52 (m, 2H), 3.44 (t, J= 4.8 Hz, 2H), 3.24 (s, 3H), 2.82 (dd, J= 16.6, 4.9 Hz, 1H), 2.80-2.68 (m, 1H), 2.66-2.51 (m, 1H), 2.46 (dd, J= 16.4, 6.4 Hz, 1H), 1.88-1.80 (m, 1H), 1.78-1.69 (m, 1H); MS (CIBP ^- ) m/z 373.2 [MH] ^- .

Example 8: 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3 -trione (Compound 107)

Example 8A: 5-[3-(benzyloxy)-7-(cyclopropylmethoxy)-1-fluoronaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00270] A mixture of Example 1H (300 mg, 0.746 mmol), cesium carbonate (486 mg, 1.491 mmol), and (bromomethyl)cyclopropane (151 mg, 1.118 mmol) in N,N -dimethylformamide (DMF) (3 mL) was stirred at room temperature for 2 h. Then 2 N Na ₂ CO ₃ (1.5 mL) was added and the reaction mixture was extracted with ethyl acetate (20 mL). The organic layer was discarded. The aqueous layer was acidified with 2 N HCl to pH 1-2 and extracted with ethyl acetate (3×25 mL). _The combined organic fractions were washed with brine, dried over _Na2SO4 and concentrated to give the title compound (230 mg, 0.504 mmol, 67.6% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO _- d6 ) δ ppm 7.77 (dd, J= 9.0, 1.5 Hz, 1H), 7.52-7.41 (m, 2H), 7.40-7.27 (m, 4H), 7.25 (dd, J= 9.0, 2.6 Hz, 1H), 7.20 (d, J= 2.6 Hz, 1H), 5.20 (s, 2H), 4.46 (s, 2H), 3.92 (d, J= 7.0 Hz, 2H), 1.31-1.17 (m, 1H), 0.61-0.50 (m, 2H), 0.38-0.29 (m, 2H); MS (CIAD ⁺ ) m/z 457.0 [M+H] ⁺ .

Example 8B: 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3 -trione

[00271] The title compound was prepared from Example 8A using the procedure described in Example 7B. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 6.42 (s, 1H), 3.93 (s, 2H), 3.73 (m, 1H), 3.31 (dd, J= 6.8, 4.1 Hz, 2H), 2.82 (dd, J= 16.5, 4.9 Hz, 1H), 2.73 (m, 1H), 2.65-2.52 (m, 1H), 2.45 (m, 1H), 1.85 (m, 1H), 1.71 (m, 1H), 1.04-0.93 (m, 1H), 0.48-0.39 (m, 2H), 0.16 (m, 2H). MS (CIAD ^- ) m/z 369.2 [MH] ^- .

Example 9: 5-(1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 108)

[00272] The product of Example 1H (1.0 g, 2.49 mmol) and acetic acid (16.2 mL) were added to 10% Pd/C, dry (1.0 g, 9.4 mmol) in a 25 mL Parr® Barnstead Hastelloy C reactor, and the mixture was stirred for 48 h under hydrogen atmosphere (140 psi) at 25°C. The mixture was then filtered through a pad of diatomaceous earth and the volatiles were removed from the filtrate under reduced pressure to give a crude residue (900 mg). A portion of the crude residue (600 mg) was purified by preparative HPLC [Waters XBridge™ C18 5 μm OBD column, 50×100 mm, flow rate 90 mL/min, gradient 3-100% acetonitrile in buffer (0.1% trifluoroacetic acid)] to afford the title compound (23 mg, 0.077 mmol, yield 5%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.46 (s, 1H), 4.33 (s, 2H), 2.67-2.60 (m, 2H), 2.56-2.51 (m, 2H), 1.69 (g, J= 5.5, 4.8 Hz, 4H); MS (CIAD ^- ) m/z 299 [MH] ^- .

Example 10: 5-[( 7S )-1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 109)

[00273] Fractions from the later eluting peak of Example 5I were concentrated to give 5-{(7S)-3-[(benzyloxy)methoxy]-1-fluoro-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl}-2-[(benzyloxy)methyl] ^-1λ6,2,5 -thiadiazolidine-1,1,3-trione (88 mg, 0.15 mmol, 28% yield). This material was hydrogenolyzed according to the procedure of Example 5J to give the title compound (30 mg, 0.091 mmol, 60% yield). The characteristics were identical to the final product of Example 11, and the absolute stereochemistry was assigned arbitrarily.

Example 11: 5-(1-fluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 110)

[00274] A solution of the product of Example 5G (203 mg, 0.622 mmol) in acetic acid (2 mL) was added to 10% Pd/C, dry (209 mg). The mixture was stirred for 13 h under 24 psi of hydrogen pressure and 25 °C. After filtration, the filtrate was concentrated to a minimum volume. The residue was purified by preparative HPLC on 2-linked Phenomenex® C8 (2) Luna® 5 µm AXIA™ 100 columns (30 mm × 150 mm each). A gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) was used at a flow rate of 50 mL/min (0-0.5 min 5% A, 0.5-8.5 min linear gradient 05-100% A, 8.7-10.7 min 100% A, 10.7-11 min linear gradient 100-05% A). Samples were injected into 1.5 mL of dimethyl sulfoxide:methanol (1:1). An Agilent 1100 Series Cleanup System was used, consisting of the following modules: Agilent 1100 Series LC/MSD SL mass spectrometer with an API electrospray source; two Agilent 1100 Series Preparative Pumps; Agilent 1100 Series Isocratic Pump; Agilent 1100 Series Diode Array Detector with a preparative flow cell (0.3 mm); Agilent Active Splitter, IFC-PAL Fraction Collector/Autosampler. The mass spectrometer makeup pump was methanol:water 3:1 with 0.1% formic acid at a flow rate of 1 mL/min. Fraction collection was automatically started when the extracted ion chromatogram (EIC) for the target mass exceeded the threshold specified in the method. The system was controlled by Agilent Chemstation software (Rev B.10.03), Agilent A2Prep, and Leap FractPal with custom Chemstation macros for data export. Fractions containing the desired product were concentrated and methanol (5 mL) was added. The suspension was sonicated and filtered. The collected solid was washed with methanol (2×1 mL) and dried in a vacuum oven at 50°C to give the title compound (19.3 mg, 0.058 mmol, 9.4% yield). ¹ H NMR (501 MHz, methanol -d ₄ ) δ ppm. 6.48 (s, 1H), 4.56 (s, 1H), 4.24 (s, 2H), 3.72-3.64 (m, 1H), 3.40 (s, 3H), 2.93 (dd, J= 16.7, 5.0 Hz, 1H), 2.84 (dt, J= 17.2, 6.4 Hz, 1H), 2.69 (dt, J = 17.0, 6.8 Hz, 1H), 2.59 (dd, J= 16.6, 6.6 Hz, 1H), 2.02-1.93 (m, 1H), 1.82 (ddt, J= 12.7, 8.0, 4.0 Hz, 1H); MS (IER ^- ) m/z 329 [MH] ^- .

Example 12: 5-(5-fluoro-7-hydroxy-3,4-dihydro-2 H -1-benzopyran-6-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 111)

Example 12A: 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene.

[00275] To a suspension of 5-bromo-1,3-difluoro-2-nitrobenzene (40 g, 168 mmol) and benzyl alcohol (18.4 mL, 176 mmol) in tetrahydrofuran (800 mL) at -60 °C was added a solution of potassium tert -butoxide (176 mL, 176 mmol, 1 M in tetrahydrofuran) slowly along the wall of the flask to keep the internal temperature below -50 °C. After complete addition, the mixture was stirred for 5 min, then quenched with saturated aqueous ammonium chloride (40 mL), diluted with water (200 mL) and ethyl acetate (200 mL), and warmed to room temperature. The aqueous layer was extracted with ethyl acetate (200 mL). The combined organic fractions were washed with brine (160 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a solid. Heptanes (500 mL) were added to the crude solid, the mixture was heated to an internal temperature of 65 °C, then slowly cooled to room temperature, and the solids were collected by filtration. The solids were washed with cold mother liquor and additional heptane (120 mL), and then dried in a vacuum oven at 60 °C to constant weight to afford 39.95 g of the title compound. The mother liquor was concentrated, and then the solids were precipitated from heptanes (100 mL) to afford an additional 7.56 g of the title compound. The overall recovery of the title compound was 47.5 g, 146 mmol, yield 87%. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm 7.63 (t, J= 1.7 Hz, 1H), 7.57 (dd, J= 9.3, 1.7 Hz, 1H), 7.46-7.32 (m, 5H), 5.36 (s, 2H).

Example 12B: 2-(benzyloxy)-4-bromo-6-fluoroaniline

[00276] To a suspension of the product from Example 12A (5.68 g, 17.4 mmol) and zinc dust (5.70 g, 87 mmol) in a mixture of tetrahydrofuran (56.8 mL) and methanol (56.8 mL) was added saturated aqueous ammonium chloride solution (28.4 mL) slowly via an addition funnel to maintain the internal temperature below 30 °C. After vigorous stirring for 1 h, the mixture was filtered through ^Celite® (5 g) and the solids were washed with ethyl acetate (56.8 mL). The filtrate was washed with brine (56.8 mL), and then the aqueous layer was extracted with ethyl acetate (28.4 mL). The combined organic layers were washed with water (28.4 mL) then brine (22.7 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (5.2 g, 17.5 mmol, 100% yield), which was used for the next step without purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.52-7.45 (m, 2H), 7.43-7.36 (m, 2H), 7.36-7.30 (m, 1H), 6.99-6.93 (m, 2 g), 5.16 (s, 2H), 4.83 (s, 2H); MS (ESI ⁺ ) m/z 296 [M+H] ⁺ .

Example 12C. N-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-2,2,2-trifluoroacetamide

[00277] To a solution of the product from Example 12B (5.6 g, 18.96 mmol) and pyridine (2.30 mL, 28.4 mmol) in acetonitrile (56 mL) at an internal temperature below 16 °C was added trifluoroacetic anhydride (3.48 mL, 24.6 mmol) slowly. After 5 min, the reaction mixture was diluted with dichloromethane (56 mL) and water (56 mL). The aqueous layer was extracted with dichloromethane (28 mL), and the combined organic layers were washed with brine (28 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (7.41 g, 18.9 mmol, 100% yield), which was used in the next step without purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 11.04 (s, 1H), 7.45-7.29 (m, 8H), 5.24 (s, 2H); MS (ESI ^- ) m/z 390 [MH] ^- .

Example 12D: Methyl 2-(N-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-2,2,2-trifluoroacetamido)acetate

[00278] To a suspension of the product from Example 12C (7.40 g, 18.9 mmol) and potassium carbonate (7.82 g, 56.6 mmol) in dimethylformamide (37 mL) was added methyl bromoacetate (2.09 mL, 22.6 mmol). The resulting suspension was heated to an internal temperature of 60 °C for 30 min, then cooled to room temperature and quenched with 1 M hydrochloric acid (74 mL). The crude aqueous mixture was extracted with ethyl acetate (74 mL, 2 x 37 mL) and the combined organic layers were washed with saturated aqueous ammonium chloride (2 x 37 mL) then brine (37 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound (9.130 g, 19.67 mmol, 104% yield), which was used in the next step without the intended purification (100% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.47-7.30 (m, 7H), 5.25 (d, J = 11.8 Hz, 1H), 5.21 (d, J= 11.9 Hz, 1H), 4.52 (d, J= 17.0 Hz, 1H), 4.29 (d, J= 17.0 Hz, 1H), 3.60 (s, 3H); MS (IER ^- ) m/z 481 [MH] ^- .

Example 12E: Methyl 2-((2-(benzyloxy)-4-bromo-6-fluorophenyl)amino)acetate

[00279] To a solution of the product from Example 12D (8.76 g, 18.87 mmol) in methanol (76.8 mL) was added a solution of sodium methoxide (10.8 mL, 47.2 mmol, 25 wt % in methanol), and the resulting solution was heated to an internal temperature of 60 °C. After 10 min, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (87.6 mL), quenched with saturated aqueous ammonium chloride (17.5 mL), and diluted with water (43.8 mL). The aqueous layer was extracted with ethyl acetate (2 x 43.8 mL) and the combined organic layers were washed with brine (26.3 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound (7.281 g, 19.77 mmol, 105% yield), which was used in the next step without purification, suggesting a 100% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.49-7.45 (m, 2H), 7.44-7.38 (m, 2H), 7.37-7.32 (m, 1H), 7.02-7.00 (m, 1H), 6.98 (dd, J= 11.8, 2.2 Hz, 1 H), 5.22 (td, J= 6.9, 2.7 Hz, 1H), 5.16 (s, 2H), 4.04 (dt, J= 7.0, 3.8 Hz, 2H), 3.59 (s, 3H); MS (ESI ⁺ ) m/z 368 [M+H] ⁺ .

Example 12F: Methyl 2-((2-(benzyloxy)-4-bromo-6-fluorophenyl)(N-(tert-butoxycarbonyl)sulfamoyl)amino)acetate

[00280] To a solution of chlorosulfonyl isocyanate (2.46 mL, 28.3 mmol) in dichloromethane at 0 °C was slowly added tert -butanol (2.71 mL, 28.3 mmol) to maintain the internal temperature below 10 °C. After stirring for 30 min, a previously prepared solution of the product from Example 12E (6.95 g, 18.88 mmol) and triethylamine (5.26 mL, 37.8 mmol) in dichloromethane (27.8 mL) was added dropwise via an addition funnel such that the internal temperature did not rise above 10 °C. After 30 min, the reaction mixture was warmed to room temperature and then quenched with water (70 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 35 mL). The combined organic layers were washed with 1 M aqueous sodium bisulfate (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was precipitated from heptanes/ethyl acetate (1:1) (24 mL), washed with cold heptanes (21 mL) and dried in a vacuum oven at 60 °C to constant weight to give the title compound (9.8188 g, 17.94 mmol, 95% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 11.31 (s, 1H), 7.48-7.41 (m, 2H), 7.40-7.34 (m, 2H), 7.34-7.26 (m, 1H), 7.22 (dd, J= 9.0, 2.1 Hz, 1H), 7.15 (t, J= 1.8 Hz, 1H), 5.24 (d, J= 13.0 Hz, 1H), 5.18 (d, J= 13.0 Hz, 1H), 4.60 (d, J= 17.8 Hz, 1H), 4.34 (d, J= 17.8 Hz, 1H), 3.52 (s, 3H), 1.28 (s, 9H); MS (IER ^- ) m/z 545 [MH] ^- .

Example 12G: Methyl 2-((2-(benzyloxy)-4-bromo-6-fluorophenyl)(sulfamoyl)amino)acetate

[00281] To a solution of the product from Example 12F (25.1 g, 45.9 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (53.0 mL, 688 mmol). After 30 min, the reaction mixture was diluted with chloroform (125 mL) and concentrated in vacuo. The crude residue was diluted with ethyl acetate (150 mL) and quenched with saturated aqueous disodium phosphate (200 mL) to a final pH of 7. The layers were separated, and the aqueous layer was extracted with ethyl acetate (125 mL). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (21.76 g, 48.7 mmol, 106% yield) as a thick yellow syrup, which was used in the next step without purification, suggesting a yield of 100%. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.53-7.49 (m, 2H),7.43-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.24-7.18 (m, 2H), 7.06 (s, 2H), 5.21 (s, 2H), 4.40 (d, J= 17.8 Hz, 1H), 4.22 (d, J= 17.8 Hz, 1H), 3.57 (s, 3H); MS (ESI ⁺ ) m/z 447 [M+H] ⁺ .

Example 12H. 5-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00282] To a solution of the product from Example 12G (29.769 g, 66.6 mmol) in tetrahydrofuran (300 mL) was slowly added sodium methoxide solution (22.8 mL, 100 mmol, 25 wt % in methanol) via syringe. After 30 min, the reaction was quenched with 1 M hydrochloric acid (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (90 mL), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in ethyl acetate (180 mL) while heating to 80 °C. Heptanes (90 mL) were added dropwise through the addition funnel while maintaining the temperature. After complete addition, the suspension was slowly cooled to room temperature and the resulting solid was collected by filtration and dried in a vacuum oven at 50°C to constant weight to give the title compound (17.564 g, 42.3 mmol, 64% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm 7.53-7.46 (m, 2H), 7.40-7.25 (m, 3H), 7.22-7.15 (m, 2H), 7.13 (s, 4H), 5.19 (s, 2H), 3.95 (s, 2H); MS (ESI ^- ) m/z 414 [MH] ^- .

Example 12I. 5-[6-(benzyloxy)-4-bromo-2-fluoro-3-(prop-2-en-1-yl)phenyl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00283] To a solution of 2,2,6,6-tetramethylpiperidine (0.474 mL, 3.13 mmol) in tetrahydrofuran (5 mL) at 0 °C was added a solution of n -butyl lithium (1.2 mL, 3 mmol, 2.5 M in hexane) slowly over 5 minutes. The resulting solution was stirred for 30 minutes, then cooled to an internal temperature of -78 °C, and a solution of the product from Example 12H (0.5 g, 1.204 mmol) in tetrahydrofuran (2.5 mL) was slowly added along the wall of the flask so that the internal temperature remained below -65 °C, then N,N,N ' ,N '-tetramethylethylenediamine (0.200 mL, 1.325 mmol). The resulting red solution was stirred for 1 h at -78 °C, and then allyl bromide (0.11 mL, 1.271 mmol) was added via syringe. The resulting solution was allowed to warm slowly to room temperature overnight, then quenched with 1 M hydrochloric acid and diluted with ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane, triethylamine (0.336 mL, 2.408 mmol) was added and the crude material was loaded onto a 40 g Gold® Teledyne ISCO column, then purified by column chromatography with a gradient of 0-10% methanol in dichloromethane (with the addition of 0.1% triethylamine) to give the title compound as the triethylamine salt (0.3915 g, 0.352 mmol, 29.2% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.53-7.04 (m, 6H), 5.90-5.70 (m, 1H), 5.14 (s, 2H), 5.01 (dt, J= 10.1, 1.7 Hz, 1H), 4.95 (dt, J= 17.2, 1.9 Hz, 1H), 3.92 (s, 2H), 3.43-3.35 (m, 2H); MS (IER ^- ) m/z 454 [MH] ^- .

Example 12J: 5-[6-(benzyloxy)-4-bromo-2-fluoro-3-(3-hydroxypropyl)phenyl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00284] To a solution of the product from Example 12I (0.3910 g, 0.703 mmol, triethylamine salt) in tetrahydrofuran (7.8 mL) was added a solution of 9-borabicyclo[3.3.1]nonane (3.4 mL, 1.7 mmol, 0.5 M in tetrahydrofuran) slowly over 5 min. After 2 h, the reaction mixture was cooled to 0 °C and 1 M aqueous sodium hydroxide (1.7 mL, 1.7 mmol) was added slowly so that the internal temperature remained below 6 °C, followed by the dropwise addition of an aqueous solution of hydrogen peroxide (0.301 mL, 4.92 mmol, 50 wt % in water) so that the internal temperature remained below 15 °C. After 1 h, the reaction mixture was quenched by adding 1 M hydrochloric acid followed by 1 M aqueous sodium thiosulfate. The crude mixture was extracted with ethyl acetate (3×) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane/acetonitrile 1:1 and triethylamine (0.196 mL, 1.405 mmol) was added, then the solution was loaded onto a 40 g Gold® Teledyne ISCO column and purified by running a gradient of 0-10% methanol in dichloromethane (with the addition of 0.1% triethylamine) to give the title compound as the triethylamine salt (0.2796 g, 0.487 mmol, 69.3% yield). ¹ H NMR (501 MHz, DMSO _-d6 ) δ ppm 7.51-7.44 (m, 2H), 7.39-7.27 (m, 3H), 7.23-7.14 (m, 1H), 4.54 (t, J= 5.1 Hz, 1H), 5.16 (s, 2H), 3.96 (s, 2H), 3.44 (k, J= 6.2 Hz, 2H), 2.66 (td, J= 8.0, 2.1 Hz, 2H), 1.66-1.56 (m, 2H); MS (IER ^- ) m/z 471 [MH] ^- .

Example 12K: 5-[7-(benzyloxy)-5-fluoro-3,4-dihydro-2H-1-benzopyran-6-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00285] In a 20 mL pressure release vial, a suspension of the product from Example 12J (0.224 g, 0.390 mmol, triethylamine salt) in N,N was added to a mixture of cesium carbonate (0.381 g, 1.170 mmol), 2-di( tert -butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos, 9 mg, 0.019 mmol), and [(2-di- tert -butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium( II ) methanesulfonate (RockPhos Pd G3 precatalyst, 16 mg, 0.019 mmol). -dimethylacetamide (6.5 mL). The resulting suspension was degassed with 5 cycles of vacuum and nitrogen backfill and then heated to 100 °C. After 4 h, the reaction mixture was cooled to room temperature and quenched with 1 M hydrochloric acid. The crude mixture was extracted with ethyl acetate (3x). The combined organic layers were then washed with saturated aqueous ammonium chloride (3x) and brine. The combined aqueous layers were re-extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude title compound as an orange oil, which was used in the next step without purification. MS (APCI ^- ) m / z 391 [MH] ^- .

Example 12L. 5-(5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00286] To a suspension of the product of Example 12K (0.191 g, 0.487 mmol) and pentamethylbenzene (0.144 g, 0.973 mmol) in dichloromethane (3.8 mL) at -78 °C was added a solution of boron trichloride (1.46 mL, 1.46 mmol, 1 M in dichloromethane) slowly along the wall of the flask so that the internal temperature did not rise above -70 °C. After complete addition, the cooling bath was removed and the reaction mixture was allowed to warm to 0 °C, then recooled to -78 °C and quenched with ethyl acetate (2 mL), then ethanol (2 mL) and warmed to room temperature. The crude reaction mixture was concentrated in vacuo to give a residue which was triturated with heptanes (3 x 5 mL) and 1:1 heptanes/ethyl acetate (2 x 5 mL). The solid was further purified by preparative reverse phase HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 column. AXIA™ (30 mm x 75 mm) using a gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to give the title compound as the ammonium salt (13.0 mg, 0.041 mmol, 8.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.08 (d, J= 1.8 Hz, 1H), 4.07 (dd, J= 5.9, 4.2 Hz, 2H), 3.89 (s, 2H), 2.55 (t, J= 6.4 Hz, 2H), 1.86 (cd, J= 6.4, 4.1 Hz, 2H); MS (ESI ^- ) m/z 301 [MH] ^- .

Example 13: 5-(5-fluoro-7-hydroxy-2,2-dimethyl-3,4-dihydro-2 H -1-benzopyran-6-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 112)

Example 13A: 5-[6-(benzyloxy)-4-bromo-2-fluoro-3-(3-methylbut-2-en-1-yl)phenyl]-1λ6,2,5 ^- thiadiazolidine-1, 1,3-trione

[00287] To a solution of 2,2,6,6-tetramethylpiperidine (0.949 mL, 6.26 mmol) in tetrahydrofuran (10 mL) at 0 °C was added a solution of n -butyl lithium (1.2 mL, 3 mmol, 2.5 M in hexane) slowly over 5 minutes. The resulting solution was stirred for 30 minutes, then cooled to an internal temperature of -78 °C, and a solution of the product from Example 12H (1.0 g, 2.4 mmol) in tetrahydrofuran (5 mL) was slowly added along the wall of the flask so that the internal temperature remained below -65 °C, then N,N,N',N'-tetramethylethylenediamine (0.400 mL, 2.65 mmol). The resulting solution was stirred for 1 h at -78 °C, and then 1-bromo-3-methylbut-2-ene (0.623 mL, 4.82 mmol, 90% pure) was added via syringe. The resulting solution was allowed to warm slowly to room temperature overnight, then quenched with 1 M hydrochloric acid and diluted with ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane, triethylamine (0.336 mL, 2.408 mmol) was added and the material was loaded onto an 80 g Gold® Teledyne ISCO column, then purified by column chromatography with a gradient of 0-10% methanol in dichloromethane (with the addition of 0.1% triethylamine) to give the title compound as the triethylamine salt (0.5033 g, 0.861 mmol, 35.8% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.65-7.08 (m, 6H), 5.74 (s, 1H), 5.19 (s, 2H), 3.96 (s, 2H), 3.40-3.33 (m, 2H), 1.73 (s, 3H), 1.65 (s, 3H); MS (IER ^- ) m/z 483 [MH] ^- .

Example 13B: 5-[6-(benzyloxy)-2-fluoro-4-hydroxy-3-(3-methylbut-2-en-1-yl)phenyl]-1λ6,2,5 ^- thiadiazolidine-1, 1,3-trione

[00288] In a 20 mL pressure release vial, cesium carbonate (0.785 g, 2.41 mmol), 2-di( tert -butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos, 19 mg, 0.040 mmol), and [(2-di- tert -butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate (RockPhos Pd G3 precatalyst, 34 mg, 0.040 mmol) were added to a suspension of the product from Example 13A (0.4693 g, 0.803 mmol, triethylamine salt) in N,N -dimethylacetamide (9.4 mL) followed by water (0.145 mL, 8.03 mmol). The resulting suspension was degassed by placing the vial under vacuum and then backfilling with nitrogen for 5 cycles. The reaction mixture was then heated to 90 °C. After 7 h, the reaction mixture was cooled to room temperature and quenched with 1 M hydrochloric acid. The crude mixture was extracted with ethyl acetate (3×), then the combined organic layers were washed with saturated aqueous ammonium chloride (3×) and brine. The combined aqueous layers were back-extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane, triethylamine (0.336 mL, 2.408 mmol) was added and the crude material was loaded onto a 24 g Teledyne ISCO Gold® column, then purified by column chromatography with a gradient of 0-10% methanol in dichloromethane (with the addition of 0.1% triethylamine) to give the title compound as the triethylamine salt (0.5033 g, 0.861 mmol, 35.8% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.55-7.43 (m, 3H), 7.34 (ddt, J= 10.1, 7.5, 2.7 Hz, 3H), 7.31-7.20 (m, 2H), 6.34 (d, J= 1.5 Hz, 1H), 5.04 (s, 2H), 3.89 (s, 2H), 3.36-3.30 (m, 2H), 1.68 (d, J= 1.3 Hz, 3H), 1.62 (d, J= 1.5 Hz, 3H); MS (IER ^- ) m/z 419 [MH] ^- .

Example 13C. 5-[3-(3-chloro-3-methylbutyl)-2-fluoro-4,6-dihydroxyphenyl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00289] To a suspension of the product of Example 13B (0.2428 g, 0.465 mmol) and pentamethylbenzene (0.138 g, 0.931 mmol) in dichloromethane (5 mL) at -78 °C was added a solution of boron trichloride (2.79 mL, 2.79 mmol, 1 M in dichloromethane) slowly along the wall of the flask so as not to raise the internal temperature above -70 °C. After complete addition, the cooling bath was removed and the reaction mixture was allowed to warm to 0 °C. The mixture was then recooled to -78 °C and quenched with ethyl acetate (1 mL), then ethanol (1 mL) and warmed to room temperature. The crude reaction mixture was concentrated in vacuo and the residue was triturated with heptanes (3 x 5 mL) to give the title compound, which was used without further purification in the next step. MS (HIBP ^- ) m/z 365 [MH] ^- .

Example 13D. 5-(5-fluoro-7-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-6-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00290] To a solution of the product of Example 13C (0.171 g, 0.465 mmol) in acetonitrile (5 mL) was added silver trifluoromethanesulfonate (0.239 g, 0.931 mmol), and the resulting suspension was heated to an internal temperature of 80 °C. After 15 h, the mixture was cooled to room temperature, diluted with methanol, and filtered through diatomaceous earth. The solid was washed thoroughly with 1:1 methanol/acetonitrile, and the filtrate was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC, Waters XBridge™ C18, 5 µm OBD, 50×100 mm, flow rate 100 mL/min, gradient 5-40% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide) at 210 nm to give the title compound as an ammonium salt (0.009 g, 0.026 mmol, yield 5.57%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 6.04 (d, J= 1.8 Hz, 1H), 3.89 (s, 2H), 2.55 (t, J= 6.8 Hz, 2H), 1.71 (t, J= 6.8 Hz, 2H), 1.25 (s, 6H); MS (IER ^- ) m/z 329 [MH] ^- .

Example 14: 5-(8-fluoro-6-hydroxy-2,2-dimethyl-3,4-dihydro-2 H -1-benzopyran-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 113)

Example 14A: 2-fluoro-4-methoxy-1-((2-methylbut-3-yn-2-yl)oxy)benzene

[00291] To a solution of 3-chloro-3-methyl-1-butyne (1.9 mL, 16 mmol) and 2-fluoro-4-methoxyphenol (3.9 mL, 35 mmol) in N,N -dimethylformamide (35 mL) at ambient temperature were added potassium iodide (9.93 g, 59.8 mmol), potassium carbonate (9.72 g, 70.4 mmol) and copper(I) iodide (0.134 g, 0.704 mmol). An exotherm was noted from 5 °C to 10 °C (internal). The reaction mixture was heated to 65 °C. After 2.5 h, 1 more equivalent of 3-chloro-3-methyl-1-butyne was added and stirring was continued at 65 °C. After 4 h, the reaction mixture was cooled to ambient temperature and water and ethyl acetate were added, followed by additional stirring for 20 min. The layers were separated and the organic phase was washed with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was passed through a plug of SiO ₂ (50 mm) in a glass funnel (140 mm diameter), eluting with 30% tert-butyl methyl ether:heptanes (1500 mL). The filtrate was concentrated and the residue was further purified by chromatography (330 g SiO ₂ ; eluting with 0% to 20% tert -butyl methyl ether:heptanes) to give 5.91 g (81%) of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 7.31 (t, J= 9.1 Hz, 1H), 6.65 (dd, J= 12.1, 3.0 Hz, 1H), 6.59 (ddd, J= 8.9, 3.0, 1.4 Hz, 1H), 3.77 (s, 3H), 2.50 (s, 1H), 1.62 (s, 6H).

Example 14B: 8-fluoro-6-methoxy-2,2-dimethyl-2H-chromene

[00292] To a solution of Example 14A (15.2 g, 73.0 mmol) in 1,2-dichloroethane (100 mL) at ambient temperature was added triphenylphosphine gold(I) bis(trifluoromethanesulfonyl)imidate (0.540 g, 0.730 mmol). After 3 h, the mixture was treated _with an additional 170 mg of gold catalyst and stirred overnight. The dark mixture was concentrated, the residue was placed on the top of a 750 g _SiO2 column and eluted with 0% to 60% _CH2Cl2 :heptanes to give an oil after concentration. The residue was taken up in 200 mL _{of CH2Cl2} , treated with _MgSO4 (5 g) and decolorizing carbon (22 g), and stirred for 90 min. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to give 10.83 g (71%) of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.53 (dd, J = 12.2, 2.8 Hz, 1H), 6.35 (dd, J = 2.9, 1.5 Hz, 1H), 6.28 (dd, J = 9.8, 1.7 Hz, 1H), 5.69 (d, J = 9.9 Hz, 1H), 3.74 (s, 3H), 1.45 (s, 6H).

Example 14C. 8-fluoro-6-methoxy-2,2-dimethylchroman

[00293] A solution of Example 14B (6.60 g, 28.5 mmol) in tetrahydrofuran (70 mL) was added to 5% Pd/C (7.19 g, 31.5 mmol) in a 250 mL pressure vessel at ambient temperature. The mixture was then shaken for 1.2 h under hydrogen (50 psi). The mixture was filtered and the filtrate was concentrated to give the title compound (6.1 g) with 90% purity. ¹ H NMR (501 MHz, CDCl ₃ ) δ ppm 6.54 (ddd, J = 12.7, 2.9, 1.4 Hz, 1H), 6.39 (dt, J= 2.9, 1.6 Hz, 1H), 3.84-3.63 (m, 3H), 2.76 (apparent t, J= 6.6 Hz, 2H), 1.81 (apparent t, J= 6.8, 2H), 1.44-1.29 (m, 6H).

Example 14D. 8-fluoro-6-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman

[00294] To a solution of Example 14C (2.00 g, 9.51 mmol) in CH ₂ Cl ₂ (40 mL) at -10 °C was added 1 M BBr ₃ in CH ₂ Cl ₂ (47.6 mL, 47.6 mmol). After 4 h, the mixture was carefully quenched by adding methanol to the flask while maintaining the internal temperature below 10 °C. Once the exotherm had ceased, excess methanol (150 mL) was added, the ice bath was removed, and the mixture was allowed to warm to ambient temperature. The mixture was concentrated on a water bath at 60 °C, and the resulting residue was reconcentrated from methanol (2×). The phenol, 8-fluoro-2,2-dimethylchroman-6-ol, was used without further purification. ¹ H NMR (400 MHz, methanol -d ₄ ) δ ppm. 6.36 (ddd, J= 12.2, 2.1, 1.4 Hz, 1H), 6.31 (ddt, J= 2.7, 1.8, 1.0 Hz, 1H), 2.72 (apparent t, J= 6.7, 0.9 Hz, 2H), 1.79 (apparent t, J= 6.8 Hz, 2H), 1.30 (s, 6H).

[00295] To a solution of 8-fluoro-2,2-dimethylchroman-6-ol (1.8 g, 9.2 mmol) in tetrahydrofuran (40 mL) at ambient temperature was added 1 M potassium 2-methylpropan-2-olate in tetrahydrofuran (13.7 mL, 13.7 mmol). After 15 min, 1-(chloromethoxy)-2-methoxyethane (1.6 mL, 14 mmol) was added and stirring was continued for 15 min. The mixture was quenched with ammonium chloride (saturated aqueous), transferred to a separatory funnel with water (100 mL) and ethyl acetate (100 mL), and shaken. The organic phase was washed with 1 M HCl (100 mL), saturated NaHCO ₃ (100 mL), water (100 mL) and brine (50 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by chromatography to remove starting material (220 g SiO ₂ , eluting with 50% to 100% tert-butyl methyl ether:heptanes) to give the title compound in 85% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 6.68 (ddt, J= 12.4, 2.9, 0.7 Hz, 1H), 6.57 (ddt, J= 2.6, 1.7, 1.0 Hz, 1H), 5.16 (s, 2H), 3.87-3.76 (m, 2H), 3.63-3.51 (m, 2H), 3.39 (s, 3H), 2.80-2.71 (m, 2H), 1.80 (t, J= 6.8 Hz, 2H), 1.36 (s, 6H).

Example 14E. 8-fluoro-7-iodo-6-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman

[00296] To a solution of Example 14D (2.28 g, 8.02 mmol) and tetramethylethylenediamine (2.4 mL, 16 mmol) in tetrahydrofuran (50 mL) at -66 °C was added 1.4 M s -BuLi in cyclohexane (8.0 mL, 11 mmol) at a rate such that the internal temperature was maintained at <-60 °C. Stirring was continued for 3 h. To this mixture was added I ₂ in tetrahydrofuran (6.7 mL, 16.84 mmol). After 15 min, the reaction mixture was allowed to warm to ambient temperature. The reaction was quenched with saturated NH ₄ Cl, transferred to a separatory funnel with water and ethyl acetate, and shaken with saturated sodium bisulfite. The organic phase was washed with 1 M HCl, saturated NaHCO ₃ , water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (94% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.77 (dd, J = 2.0, 1.1 Hz, 1H), 5.22 (s, 2H), 3.81-3.72 (m, 2H), 3.53-3.43 (m, 2H), 3.24 (s, 3H), 2.79-2.64 (m, 2H), 1.77 (m, 2H), 1.29 (s, 6H).

Example 14F. tert-Butyl ({8-fluoro-6-[(2-methoxyethoxy)methoxy]-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-7-yl}amino)acetate

[00297] To a solution of Example 14E (3.00 g, 7.31 mmol) and tert -butyl 2-aminoacetate (1.2 mL, 8.8 mmol) in dioxane (50 mL) at ambient temperature were added cesium carbonate (4.77 g, 14.6 mmol), [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3, 0.663 g, 0.731 mmol), and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 0.393 g, 0.731 mmol). The mixture was degassed (3×vacuum/ _N2 purge); then heated to 98°C. After 90 min, less than 10% conversion was observed. Additional BrettPhos (0.1 equivalent) and BrettPhos Pd G3 (0.1 equivalent) were added and heating was continued. After 2 h, the reaction was complete. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate (emulsion). The organic phase was washed with additional water (emulsion) and brine, then concentrated. The residue was purified by chromatography (220 g _SiO2 , eluting with 0% to 50% ethyl acetate:heptanes) to give 2.56 g (67%) of the title compound. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 6.60 (dt, J= 2.1, 0.9 Hz, 1H), 5.20 (s, 2H), 4.41 (td, J= 6.2, 2.6 Hz, 1H), 3.96 (dd, J= 6.0, 2.1 Hz, 2H), 3.90-3.79 (m, 2H), 3.63-3.52 (m, 2H), 3.39 (s, 3H), 2.66 (m, 2H), 1.77 (m, 2H), 1.45 (s, 9H), 1.34 (s, 6H).

Example 14G. tert-Butyl ([(tert-butoxycarbonyl)sulfamoyl]{8-fluoro-6-[(2-methoxyethoxy)methoxy]-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-7-yl}amino)acetate

[00298] To a solution of sulfurisocyanate chloride (0.80 mL, 9.3 mmol) in CH ₂ Cl ₂ (20 mL) at 5 °C was added 2-methylpropan-2-ol (0.89 mL, 9.3 mmol). After 30 min, a solution of Example 14F (2.56 g, 6.19 mmol) and triethylamine (1.7 mL, 12 mmol) in CH ₂ Cl ₂ (20 mL) was added and the mixture was stirred for 1 h. The reaction mixture was transferred to a separatory funnel with CH ₂ Cl ₂ and washed with brine. The organic phase was concentrated, the residue was dissolved in tert-butyl methyl ether and washed with water (emulsion) and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to give 3.32 g (81%) of the title compound with 90% purity. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm. 6.82-6.77 (m, 1H), 5.22 (d, J = 7.0 Hz, 1H), 5.15 (d, J= 7.0 Hz, 1H), 4.66 (d, J= 17.4 Hz, 1H), 4.12 (d, J= 17.4 Hz, 1H), 3.79-3.67 (m, 2H), 3.47 (t, J= 4.8 Hz, 2H), 3.24 (s, 3H), 2.74 (apparent t, J= 6.8 Hz, 2H), 1.77 (apparent t, J = 6.9 Hz, 2H), 1.43 (d, J= 10.7 Hz, 9H), 1.32 (s, 9H), 1.30 (s, 3H), 1.27 (s, 3H).

Example 14H. 5-(8-fluoro-6-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00299] To a solution of Example 14G (1.78 g, 3.00 mmol) in 2-methyltetrahydrofuran (30 mL) at ambient temperature was added 6% Mg( _OCH3 ) ₂ in _CH3OH (15.9 mL, 9.01 mmol), and the mixture was heated to 65°C. After 36 h, the reaction mixture was cooled to ambient temperature and filtered through diatomaceous earth (eluting with 2-methyltetrahydrofuran). The filtrate was concentrated and filtered again through a Whatman polytetrafluoroethylene (PTFE) membrane filter (0.45 μm×25 mm; elution with 2-methyltetrahydrofuran), concentrated to give 5-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-2,2-dimethyl-3,4-dihydro-2 H -1-benzopyran-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, which was used directly in the next reaction. MS (ESI ^- ) m/z 325 [MH] ^- .

[00300] To a neat sample of 5-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-2,2-dimethyl-3,4-dihydro-2 H -1-benzopyran-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.040 g, 0.096 mmol) at ambient temperature was added 4 M HCl in dioxane (0.5 mL, 2 mmol). After 1 h, the reaction mixture was triturated with ether, sonicated and filtered to give 3.3 mg (10%) of the title compound. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.74 (s, 1H), 6.42 (d, J= 2.0 Hz, 1H), 3.57 (s, 2H), 2.63 (apparent t, J= 6.7 Hz, 2H), 1.73 (apparent t, J= 6.7 Hz, 2H), 1.26 (s, 6H).

Example 15: 5-(1,4-difluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 114)

Example 15A: 5-[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00301] To a mixture of the product of Example 1F (300 mg, 0.603 mmol) in N,N -dimethylformamide (6.73 mL) was added Selectfluor® (256 mg, 0.724 mmol), and the solution was heated to 65 °C. After 90 min, the mixture was cooled to room temperature and the excess oxidizing agent was quenched with a solution of sodium thiosulfate pentahydrate (404 mg, 1.63 mmol) in water (3.3 mL). After stirring for 15 min, water (10 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with saturated aqueous ammonium chloride (2×10 mL) and brine (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give methyl {[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl](sulfamoyl)amino}acetate as a viscous orange oil, which was used in the next step without further purification. MS ( ^APCI ) m/z 516 [M+H] ⁺ .

[00302] To a solution of methyl {[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl](sulfamoyl)amino}acetate from the previous reaction in tetrahydrofuran (2.69 mL) at room temperature was added a solution of sodium methoxide (207 μL, 0.905 mmol) (25 wt % in methanol) via syringe, and the resulting solution was stirred at room temperature. After 5 min, the reaction was quenched with 1 M hydrochloric acid (3 mL) and diluted with ethyl acetate (3 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 1 mL). The combined organic layers were washed with water (2 x 1 mL), saturated aqueous ammonium chloride (2 x 1 mL), and brine (1 x 1 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (24 g _SiO2 , _CH2Cl2 to 10% methanol/ _{CH2Cl2 )} to give the title compound along with minor inseparable impurities. The product was used in the next step without further purification. MS (APCI ⁺ ) m _/ z 484 [M+H] ⁺ .

Example 15B: 5-[3-(benzyloxy)-1,4-difluoro-7-methoxynaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00303] A mixture of the product of Example 15A (301 mg, 0.623 mmol), [(2-di- tert -butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-methanesulfonate biphenyl)-2-(2-aminobiphenyl)]palladium(II) (RockPhos Pd G3 precatalyst, 16.1 mg, 0.019 mmol), and cesium carbonate (609 mg, 1.87 mmol) was placed under vacuum and stirred for 5 min, then the flask was flushed with nitrogen and a premix of N,N -dimethylformamide (3.11 mL) and anhydrous methanol (126 µL, 3.11 mmol) was added. The resulting suspension was degassed with five additions of vacuum/nitrogen and then heated to an internal temperature of 80 °C. After 15 min, the reaction mixture was cooled to room temperature, quenched by slow addition of 1 M hydrochloric acid (5 mL), and diluted with ethyl acetate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4 x 5 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (12 g SiO ₂ , CH ₂ Cl ₂ to 10% methanol/CH ₂ Cl ₂ ) to afford the title compound along with minor inseparable impurities. The product was used in the next step without further purification. MS ( ^APCI ) m/z 435 [M+H] ⁺ .

Example 15C. 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00304] A mixture of the product of Example 15B (38.7 mg, 0.089 mmol) and pentamethylbenzene (39.6 mg, 0.267 mmol) in dichloromethane (445 μL) was cooled to an internal temperature of -76 °C under a dry nitrogen atmosphere. A 1 M solution of boron trichloride (178 μL, 0.178 mmol) in CH ₂ Cl ₂ was then added dropwise over 15 min to keep the internal temperature below -72 °C. After 15 min, the reaction was quenched at -75 °C with CH ₂ Cl ₂ /methanol (10:1, 230 μL) via cannula transfer under a nitrogen atmosphere. The mixture was then slowly warmed to room temperature under a nitrogen atmosphere. Volatiles were removed in vacuo to yield a brown solid which was purified by HPLC (Phenomenex® Luna® 10 µM C18(2) 100 , AXIA™ column (00G-4253-U0-AX), 250 x 30 mm, flow rate 50 mL/min, gradient 5-95% acetonitrile in buffer (0.025 M aqueous ammonium acetate) to give the title compound (10.3 mg, 0.030 mmol, 34% yield). ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 7.84 (dd, J = 9.3, 1.4 Hz, 1 H), 7.30 (t, J = 1.5 Hz, 1 H), 7.23 (dd, J = 9.3, 2.5 Hz, 1 H), 4.41 (s, 2 H), 3.91 (s, 3 H); MS (IER ^- ) m/z 343 [MH] ^- .

Example 15D. 5-(1,4-difluoro-3-hydroxy-7-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00305] To a mixture of 10% Pd-C (23.18 mg, 0.218 mmol) in ethanol (10 mL) was added Example 15C (50 mg, 0.109 mmol) at 25 °C, and then the mixture was stirred for 24 h at 60 °C under H ₂ (140 psi). The mixture was filtered, and the filtrate was concentrated under a stream of N ₂ at 25 °C to give the crude product. The reaction was repeated on the same scale. The crude products from both reactions were combined and purified by preparative HPLC on a Welch Ultimate® AQ-C18 150*30 mm*5 μm column eluting with 5-100% acetonitrile in water with 0.075% trifluoroacetic acid at a flow rate of 25% mL/min to give the title compound (2 mg, 2% yield). ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 4.32 (s, 2H), 3.62 (m, 1H), 3.30 (s, 3H), 2.88-2.69 (m, 2H), 2.60 (m, 2H), 1.99-1.70 (m, 2H); MS (ESI ⁺ ) m/z 366.0 [M+18] ⁺ .

Example 16: 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 115)

Example 16A : 5-[7-{[2-(azetidin-1-yl)ethyl]amino}-3-(benzyloxy)-1-fluoronaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00306] A mixture of 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 1G, 93 mg, 0.2 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3, 10.88 mg, 0.012 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 6.44 mg, 0.012 mmol), cesium carbonate (195 mg, 0.600 mmol) and 2-(azetidin-1-yl)ethanamine (40.1 mg, 0.400 mmol) in 2-methylbutan-2-ol (2 mL) were bubbled and filled with nitrogen five times. The mixture was then heated at 105 °C for 3 h. The mixture was cooled to room temperature and CH ₂ Cl ₂ /CH ₃ OH (10:1, 50 mL) was added to the mixture, followed by 4 M HCl in dioxane (0.2 mL). The mixture was filtered, _the filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (12 g), eluting with _CH2Cl2 / _CH3OH (0 to 65%) to give the title compound (85 mg, 0.175 mmol, 88% yield) as a solid. MS (ESI-) m/z 424 [MH] ^- .

Example 16B: 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00307] To a mixture of Example 16A (85 mg, 0.175 mmol) and 1,2,3,4,5-pentamethylbenzene (59.8 mg, 0.403 mmol) in CH ₂ Cl ₂ (5 mL) at -78 °C was added trichloroborane (1754 µL, 1.754 mmol). The mixture was stirred at -78 °C for 5 min and then warmed to 0 °C for 30 min. The mixture was quenched with ethanol (4 mL) and then concentrated. The residue was washed with CH ₂ Cl ₂ (4×4 mL) and dried to give the title compound (73 mg, 0.169 mmol, 97% yield) as the HCl salt. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.38 (lat s, 1H), 10.12 (lat s, 1H), 7.55 (lat s, J= 8 Hz, 1H), 7.03 (dd, J= 8, 2 Hz, 1H), 6.97 (s, 1H), 6.75 (d, J= 2 Hz, 1H), 4.50 (s, 2H), 4.11 (m, 2H), 4.06 (m, 2H), 3.37 (m, 4H), 2.40 (m, 1H), 2.25 (m, 1H). MS (IER ^- ) m/z 393 [MH] ^- .

Example 16C 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00308] To Example 16B (72 mg, 0.167 mmol) in acetic acid (4 mL) was added 10% Pd/C (216 mg, 2.16 mmol). The mixture was stirred for 5 days at room temperature under hydrogen atmosphere (110 psi). Then methanol (20 mL) was added and the mixture was filtered. The filtrate was concentrated and the residue was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm column, 25×150 mm, flow rate 80 mL/min, 5-60% acetonitrile gradient in buffer (0.025 M aqueous ammonium bicarbonate solution, pH adjusted to 10 with ammonium hydroxide)] to give the title compound (4 mg, 0.01 mmol, 6% yield). ¹ H NMR (500 MHz, DMSO _-d6 ) δ ppm 6.43 (s, 1H), 3.92 (s, 2H), 3.41 (t, J= 8 Hz, 2H), 3.17 (1H), 2.97 (m, 1H), 2.91 (m, 1H), 2.71 (m, 6H), 2.32 (m, 1H), 2.08 (m, 2H), 1.97 (m, 2H), 1.52 (m, 1H); MS (ESI ⁺ ) m/z 39 [M+H] ⁺ .

Example 17: 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 116)

Example 17A: 5-{3-(benzyloxy)-1-fluoro-7-[(3,3,3-trifluoropropyl)amino]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00309] A mixture of 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 1G, 170 mg, 0.365 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3, 23.18 mg, 0.026 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 23.53 mg, 0.044 mmol), cesium carbonate (357 mg, 1.096 mmol) and 3,3,3-trifluoropropan-1-amine (66.1 mg, 0.585 mmol) in 2-methylbutan-2-ol (6 mL) were bubbled and filled with N ₂ five times, and then the mixture was heated at 105 °C for 2 h. The mixture was cooled to room temperature and CH ₂ Cl ₂ /CH ₃ OH (10:1, 50 mL) was added to the mixture, followed by 4 M HCl in dioxane (0.2 mL). The mixture was filtered, _the filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (12 g), eluting with _CH2Cl2 / _CH3OH (0 to 65%) to give the title compound (159 mg, 0.32 mmol, 87% yield). MS (ESI ^- ) m/z 496 [MH] ^- .

Example 17B: 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl} ^-1λ6,2,5 -thiadiazolidine-1,1,3-trione

[00310] To a mixture of Example 17A (158 mg, 0.318 mmol) and 1,2,3,4,5-pentamethylbenzene (108 mg, 0.731 mmol) in _CH2Cl2 (5 mL) at -78 °C was added trichloroborane (3176 μL, 3.18 mmol). The mixture was stirred at -78 °C for 5 min and then warmed to 0 °C over 20 min. The mixture was quenched _with ethanol (4 mL) and concentrated. The residue was washed with heptane (4×4 mL), the resulting solid was dissolved in CH ₃ OH (5 mL) and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm, 25×150 mm column, flow rate 80 mL/min, gradient 5-70% CH ₃ OH in water (0.01% trifluoroacetic acid) to give the title compound (100 mg, 0.318 mmol, 77% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.81 (br s, 1H), 7.53 (br d, J= 8 Hz, 1H), 7.01 (dd, J= 8, 2 Hz, 1H), 6.95 (s, 1H), 6.68 (d, J= 2 Hz, 1H), 4.40 (s, 2H), 3.37 (t, J= 8 Hz, 2H), 2.59 (m, 2H); MS (IER ^- ) m/z 496 [MH] ^- .

Example 17C: 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00311] To Example 17B (80 mg, 0.196 mmol) in acetic acid (3 mL) was added 5% Pd/C (wet, 160 mg, 0.7 mmol). The mixture was stirred at room temperature for 2 days under hydrogen atmosphere (110 psi). Then CH ₃ OH (20 mL) was added and the mixture was filtered. The filtrate was concentrated and the residue was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm, 25×150 mm column, flow rate 80 mL/min, 5-90% acetonitrile gradient in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (8.5 mg, 0.021 mmol, yield 10.5%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.15 (br s, 1H), 7.10 (br s, 1H), 6.46 (s, 1H), 3.93 (s, 2H), 3.20 (m, 2H), 3.04 (m, 2H), 2.77 (m, 2H), 2.63 (m, 2H), 2.10 (m, 1H), 1.52 (m, 2H); MS (ESI ^- ) m/z 410 [MH] ^- .

Example 18: 5-{(7 S )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 117)

Example 18A: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00312] To a solution of the product from Example 22I (0.9659 g, 1.92 mmol) and isoamylamine (0.251 g, 2.88 mmol) in acetonitrile (19.2 mL) at room temperature was added sodium cyanoborohydride (0.145 g, 2.3 mmol). After 18 h, the reaction mixture was diluted with acetonitrile (10 mL), quenched with ammonium hydroxide (0.436 mL, 23 mmol), and then water (2 mL) was added. Celite® (5 g) was then added and the mixture was concentrated in vacuo. The residue was purified by reversed phase chromatography by dry loading onto a Teledyne ISCO 100 g C18 column using a gradient of 5-50% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.4694 g, 0.991 mmol, 51.7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 8.42 (s, 2H), 6.77 (d, J= 1.4 Hz, 1H), 5.21 (s, 2H), 3.93 (d, J= 1.1 Hz, 2H), 3.77-3.70 (m, 2H), 3.48-3.42 (m, 3H), 3.23 (s, 3H), 3.13 (dd, J= 16.5, 5.6 Hz, 1H), 3.03 (dd, J= 9.6, 6.2 Hz, 2H), 2.92-2.72 (m, 2H), 2.62-2.51 (m, 1H), 2.22-2.15 (m, 1H), 1.79-1.60 (m, 2H), 1.50 (dt, J= 10.6, 7.0 Hz, 2H), 0.93 (s, 3H), 0.91 (s, 3H); MS (CIBP ⁺ ) 474 [M+H] ⁺ .

Example 18B: 5-{(7S)-1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl} -1 λ ^6,2,5 -thiadiazolidine-1,1,3-trione

[00313] The product of Example 18A (205.7 mg, 0.434 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 supplied by a 350 psi dewar of bone dry, non-certified _CO2 with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 45% cosolvent: _CO2 . Fraction collection was time triggered. The instrument was equipped with a 21 mm id x 250 mm long CHIRALPAK® IC column with 5 μm particles. The enantiomer peak eluted early to give the title compound (69.9 mg, 0.148 mmol, 68% yield). ^1H NMR and MS data were identical to those of Example 18A.

Example 18C. 5-{(7S)-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 117)

[00314] To a suspension of the product of Example 18B (20 mg, 0.042 mmol) in acetonitrile (0.8 mL) was added a solution of hydrogen chloride (0.053 mL, 0.211 mmol, 4 M in dioxane). After 2 h, the solid was collected by filtration, washed with acetonitrile (0.5 mL), and dried in a vacuum oven at 50 °C to give the title compound (9.5 mg, 58.4% yield). The ¹ H NMR and MS data were identical to those of Example 3.

Example 19: 5-{(7 R )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 118)

Example 19A: 5-{(7R)-1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00315] The product of Example 18A (205.7 mg, 0.434 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 supplied by a 350 psi dewar of bone dry, non-certified _CO2 with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 45% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm x 250 mm id CHIRALPAK® IC column with 5 μm particles. The late eluting enantiomer peak gave the title compound (60.3 mg, 0.127 mmol, 58.6% yield). ¹ H NMR and MS data were identical to those of Example 18A. Crystals suitable for X-ray crystallography were grown by slow evaporation of the methanolic solution. X-ray crystallographic analysis showed that the absolute stereochemistry is ( R ).

Example 19B: 5-{(7R)-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl} ^-1λ6.2 , 5-thiadiazolidine-1,1,3-trione (Compound 117)

[00316] To a suspension of the product of Example 19A (60 mg, 0.127 mmol) in acetonitrile (1.2 mL) was added a solution of hydrogen chloride (0.158 mL, 0.634 mmol, 4 M in dioxane). After 2 h, the reaction mixture was diluted with acetonitrile (1 mL), quenched with ammonium hydroxide (0.014 mL, 0.760 mmol), and then diluted with water (0.5 mL). Celite® (1 g) was added and the resulting suspension was concentrated. The crude residue was loaded onto a 100 g C18 column and purified by reverse phase liquid chromatography, flow rate 60 ml/min, gradient 10-50% (10 column volumes) then 50-100% (6 column volumes), then wash with 100% (1 column volume) methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice), monitoring at 206 nM, to give the title compound (33.3 mg, 0.086 mmol, 68.2% yield). ¹ H NMR and MS were identical to the product from Example 3.

Example 20: 5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 119)

Example 20A: 5-{3-(benzyloxy)-7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoronaphthalene-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3- trion

[00317] Example 1H (511 mg, 1.270 mmol), 3-(bromomethyl)-1,1-difluorocyclobutane (470 mg, 2.54 mmol), and cesium carbonate (1241 mg, 3.81 mmol) were combined in N,N -dimethylformamide (DMF) (5 mL). The reaction mixture was heated overnight at 50 °C. The material was diluted with 1 M HCl (aqueous) and extracted with ethyl acetate. The organic fraction was washed with saturated NH ₄ Cl (2×) and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give the title compound (409 mg, 64% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 7.79 (dd, J =9.0, 1.5 Hz, 1H), 7.55-7.45 (m, 2H), 7.43-7.19 (m, 6H), 5.20 (s, 2H), 4.47 (s, 2H), 4.14 (d, J =6.3 Hz, 2H), 2.81-2.49 (m, 5H).

Example 20B: 5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00318] Example 20A (406 mg, 0.802 mmol) in tetrahydrofuran (THF) (4.0 mL) was added to 5% Pd/C (wet JM #9) (108 mg, 0.451 mmol) in a 20 mL RS10 Hastelloy C reactor. The reactor was purged with argon. The mixture was stirred at 1200 rpm under 65 psi of hydrogen at 25 °C. After 16.3 h, the reactor was vented. Hydrogen uptake ceased between 9-10 h. The mixture was filtered through a filter funnel with a polyethylene frit packed with diatomaceous earth in the form of tetrahydrofuran (THF) solution (4.0 mL). The catalyst was washed sequentially with methanol (2×) and again with THF. The combined filtrate and washings were concentrated on a rotary evaporator. The residue was placed under house vacuum for 10 min to produce a foam. The material was triturated with dichloromethane/heptanes to give a solid which was collected by filtration and dried under reduced pressure (267 mg, 80% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.68 (dd, J = 9.0, 1.5 Hz, 1H), 7.24-7.13 (m, 2H), 7.03 (s, 1H), 4.43 (s, 2H), 4.11 (d, J = 6.3 Hz, 2H), 2.80-2.48 (m, 5H); MS (ESI ^- ) m/z 414.9 [MH] ^- .

Example 20C. 5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1 λ ^6,2,5 -thiadiazolidin-1 ,1,3-trione

[00319] Example 20B (100 mg, 0.240 mmol) in acetic acid (AcOH) (2.0 mL) was added to 10% Pd/C, dry (26.9 mg, 0.025 mmol) in an RS10 Hastelloy C reactor. The reactor was purged with nitrogen and the mixture was stirred under 130 psi of hydrogen at 25 °C for 42.75 hours. The reactor was vented and the reaction mixture was filtered, but the reaction was considered incomplete. The filtrate was combined with 5% Pd/C (wet JM # 9) (377 mg, 1.289 mmol) and repressurized under hydrogen (119 psi) for 95.6 hours and then under hydrogen (136 psi) for an additional 24.56 hours. The mixture was filtered through a polyethylene frit filter funnel packed with diatomaceous earth washed with methanol. The filtrate was concentrated and the residue was purified by preparative reverse-phase HPLC on a Phenomenex® Luna® C8(2) 5 µm 100 column. AXIA™ (50 mm x 30 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used at a flow rate of 40 mL/min (0-0.5 min 25% A, 0.5-8.0 min linear gradient 25-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-25% A, 9.1-10.0 min 25% A) to give the title compound (10.2 mg, 10% yield). ¹ H NMR (500 MHz, 9:1 v/v DMSO- d ₆ /D ₂ O) δ ppm 6.43 (s, 1H), 3.99 (s, 2H), 3.80-3.71 (m, 1H), 3.56-3.44 (m, 2H), 2.84-2.53 (m, 5H), 2.45 (dd, J = J = 16.5, 6.2 Hz, 1H), 2.33-2.18 (m, 3H), 1.92-1.79 (m, 1H), 1.79-1.67 (m, 1H); MS (IER ^- ) m/z 418.9 [MH] ^- .

Example 21: 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 120)

[00320] The title compound was prepared using the methodologies described in Example 17, replacing 3,3,3-trifluoropropan-1-amine with 4,4,4-trifluorobutan-1-amine. ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 9.18 (br s, 1H), 7.26 (b s, 1H), 6.47 (s, 1H), 3.93 (s, 2H), 3.07 (m, 4H), 2 .77 (m, 2H), 2.41 (m, 2H), 2.21 (m, 1H), 1.84 (m, 2H), 1.68 (m, 2H).; MS (IER ^- ) m/z 424 [MH] ^- .

Example 22: 5-{1-fluoro-3-hydroxy-7-[(4-methoxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 121)

Example 22A: 6-bromo-8-fluoro-3,4-dihydronaphthalen-2(1H)-one

[00321] To a suspension of 4-bromo-2-fluorophenylacetic acid (10.0 g, 42.9 mmol) in dichloroethane (100 mL) at room temperature was added N,N -dimethylformamide (5 drops), followed by 2 M oxalyl chloride in dichloromethane (23.6 mL, 47.2 mmol). After 90 min, the reaction was complete and was used directly in the next reaction without concentration or further workup. A small sample was removed for analytical analysis. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.51 (td, J= 9.4, 2.0 Hz, 1H), 7.40-7.26 (m, 2H), 3.63 (s, 2H).

[00322] To a solution of aluminum trichloride (7.44 g, 55.8 mmol) in dichloromethane (200 mL) at -10 °C was added the acid chloride solution from above at such a rate as to maintain the internal temperature below -2 °C. Stirring was continued for 15 min. A weak stream of ethylene was introduced into the mixture (internal temperature -4 °C). After 1 h, the gas flow was stopped and the mixture was stirred for an additional 10 min at -2 °C. The reaction was slowly quenched with ice water using 2 mL aliquots from a pipette until the internal temperature ceased to rise (approximately 16 to 20 mL of water was added; internal temperature was 10 °C). Additional water (500 mL) was then added, the ice bath was removed and the mixture was stirred for 10 min to a final internal temperature of 20 °C. _The mixture was transferred to a separatory funnel and the organic phase was washed with brine, then dried ( _Na2SO4 ), filtered and concentrated to give 12.6 g of the title compound which was used in the next step without purification. A small sample was removed for analytical analysis. ¹ H NMR (500 MHz, methanol - _d4 ) δ ppm 7.11 (dd, J= 2.0, 1.1 Hz, 1H), 7.06 (dd, J= 9.2, 1.9 Hz, 1H), 2.82 (m, 2H), 1.97 (m, 2H).

Example 22B: 6' - bromo-8' -fluoro-3 ',4' - dihydro-1'H -spiro[[1,3]dioxolane-2,2' -naphthalene]

[00323] To a solution of the product from Example 22A (10.4 g, 42.9 mmol) and ethylene glycol (14.5 mL, 257 mmol) in toluene (100 mL) at room temperature was added 4-methylbenzenesulfonic acid hydrate (1.63 g, 8.58 mmol); the flask was fitted with a Dean-Stark trap and heated to reflux. After 1 h, the reaction mixture was cooled to room temperature, transferred to a separatory funnel with ethyl acetate (500 mL), and washed with saturated aqueous sodium bicarbonate (2 x 300 mL), water (200 mL), and brine (200 mL). The organic fraction was then dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was purified by chromatography (750 g silica; 1 h gradient elution from 0% to 20% ethyl acetate:heptanes) to afford 8.74 g (42.9 mmol, 90% purity, 63.8% yield) of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.29 (dd, J = 9.2, 1.9 Hz, 1H), 7.23 (dd, J = 2.0, 1.0 Hz, 1H), 4.00-3.90 (m, 4H), 2.91 (apparent t, J = 6.7 Hz, 2H), 2.76 (s, 2H), 1.85 (apparent t, J = 6.7 Hz, 2H).

Example 22C 8 ' -fluoro-3 ' ,4 ' -dihydro-1 ' H-spiro[[1,3]dioxolane-2,2 ' -naphthalene]-6 ' -ol

[00324] To a solution of the product of Example 22B (12.1 g, 42.2 mmol) were added water (3.8 mL, 210 mmol) and cesium carbonate (28 g, 84 mmol) in N,N -dimethylacetamide (100 mL) at room temperature. The precatalyst was t-BuBrettPhosPd G3 (1.4 g, 1.7 mmol). The reaction mixture was degassed (3×vacuum/nitrogen purge) followed by heating to 90 °C. After 90 min, the reaction mixture was cooled to room temperature and transferred to a separatory funnel with water (200 mL) and ethyl acetate (600 mL). To this was added 1 M hydrochloric acid (500 mL) to adjust the pH of the aqueous phase to 3. The layers were separated and the organic phase was washed with water (3 x 400 mL) and brine (1 x 400 mL); then dried (Na ₂ SO ₄ ), filtered and concentrated. The two reaction batches were combined and purified by chromatography (750 g silica; gradient elution from 0% to 40% ethyl acetate:0.1% triethylamine in heptanes) to give 9.34 g (41.8 mmol, 49%) of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.52 (s, 1H), 6.36 (d, J= 9.2 Hz, 2H), 3.99-3.87 (m, 4H), 2.80 (t, J= 6.7 Hz, 2H), 2.68 (s, 2H), 1.80 (t, J= 6.7 Hz, 2H); MS (IER ^- ) m/z 223 [MH] ^- .

Example 22D. 8 ' -fluoro-6 ' -[(2-methoxyethoxy)methoxy]-3 ' ,4 ' -dihydro-1 ' H-spiro[[1,3]dioxolane-2,2 ' -naphthalene]

[00325] To a solution of the product from Example 22C (3.6628 g, 16.34 mmol) and 2-methoxyethoxymethyl chloride (2.77 mL, 24.5 mmol) in tetrahydrofuran (72 mL) at room temperature was added N,N -diisopropylethylamine (5.71 mL, 32.7 mmol). The resulting solution was then heated to an internal temperature of 60 °C. After 24 h, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (36 mL) and water (36 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with 1 M aqueous sodium bisulfate (36 mL), then brine (18 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was loaded onto an 80 g silica gel column in dichloromethane and purified by running a gradient of 0-30% ethyl acetate in heptanes containing 0.1% triethylamine to give the title compound (2.9903 g, 9.57 mmol, 58.6% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm. 6.64 (dd, J= 2.5, 1.1 Hz, 1H), 6.61 (dd, J= 11.0, 2.4 Hz, 1H), 5.20 (s, 2H), 4.08-3.98 (m, 4H), 3.83-3.76 (m, 2H), 3.59-3.52 (m, 2H), 3.38 (s, 3H), 2.96 (t, J= 6.7 Hz, 2H), 2.85 (s, 2H), 1.96-1.89 (m, 2H); MS (APCI ⁺ ) m/z 237 [M-(OCH ₂ CH ₂ OCH ₃ )] ⁺ .

Example 22E. 8' - fluoro-7' - iodo-6 ' -[(2-methoxyethoxy)methoxy]-3 ',4' - dihydro- 1'H-spiro[[1,3]dioxolane-2,2' - naphthalene]

[00326] To a solution of 2,2,6,6-tetramethylpiperidine (4.30 mL, 25.3 mmol) in tetrahydrofuran (100 mL) at 0 °C was added a solution of n -butyl lithium (9.49 mL, 23.72 mmol, 2.5 M in hexane) dropwise to maintain the internal temperature below 7 °C. After 30 minutes, the solution was cooled to an internal temperature of -74 °C, and then a solution of the product of Example 22D (4.94 g, 15.82 mmol) in tetrahydrofuran (25 mL) was slowly added along the wall of the flask at a rate such that the internal temperature remained below -70 °C, followed by the dropwise addition of N,N,N ',N' -tetramethylethylenediamine (3.58 mL, 23.72 mmol). The resulting solution was stirred for 2 h at -78 °C, then a solution of iodine (8.03 g, 31.6 mmol) in tetrahydrofuran (25 mL) was added dropwise such that the internal temperature remained below -65 °C. After complete addition, the reaction mixture was allowed to warm to 0 °C. The resulting suspension was quenched with a 1:1 mixture of saturated aqueous ammonium chloride and 1 M aqueous sodium thiosulfate (50 mL), stirred for 5 min at room temperature, and then extracted with ethyl acetate (50 mL, 2 x 25 mL). The combined organic layers were washed with water (50 mL) and brine (20 mL), then dried over sodium sulfate, filtered, and partially concentrated in vacuo to about 50 mL total volume. Silica (20 g) was added, and the resulting suspension was concentrated in vacuo. The resulting yellow powder was dry loaded onto a 120 g silica gel column and eluted with a gradient of 0-30% ethyl acetate in heptanes containing 0.1% triethylamine to give the title compound (5.6776 g, 12.96 mmol, 82% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 6.73 (d, J= 1.4 Hz, 1H), 5.30 (s, 2H), 4.09-3.97 (m, 4H), 3.88-3.76 (m, 2H), 3.60-3.52 (m, 2H), 3.38 (s, 3H), 2.96 (t, J= 6.7 Hz, 2H), 2.88 (s, 2H), 1.92 (t, J= 6.7 Hz, 2H); MS (CIAD ⁺ ) m/z 363 [M-(OCH ₂ CH ₂ OCH ₃ )] ⁺ .

Example 22F. tert-butyl ({8' - fluoro-6 ' -[(2-methoxyethoxy)methoxy]-3 ',4' - dihydro- 1'H-spiro[[1,3]dioxolane-2,2' -naphthalene]-7' - yl}amino)acetate

[00327] Cesium carbonate (7.70 g, 23.63 mmol), BrettPhos (0.127 g, 0.236 mmol), BrettPhos Pd G3 precatalyst (0.214 g, 0.236 mmol), and the product from Example 22E (5.1776 g, 11.81 mmol) were combined in a 500 mL round bottom flask. The flask was placed under vacuum for 5 min and backfilled with nitrogen. 1,4-dioxane (104 mL) was added followed by tert- butyl 2-aminoacetate (1.94 mL, 14.18 mmol). The resulting suspension was degassed with 5x vacuum/nitrogen, stirred for 5 min at room temperature, and then heated to an internal temperature of 90 °C. After 2 h, the mixture was cooled to below 40 °C and another portion of BettPhos (0.127 g, 0.236 mmol) and BrettPhos Pd G3 precatalyst (0.214 g, 0.236 mmol) were added. The resulting mixture was degassed with vacuum/nitrogen three times and heating was resumed to 90 °C. After 90 min, the reaction mixture was cooled to below 40 °C and another portion of BettPhos (0.127 g, 0.236 mmol) and BrettPhos Pd G3 precatalyst (0.214 g, 0.236 mmol) were added. The mixture was degassed with vacuum/nitrogen three times and heating was resumed to 90 °C. After 24 h, the reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (15 mL), diluted with water (35 mL) and extracted with ethyl acetate (50 mL, 2 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was loaded onto an 80 g silica gel column in dichloromethane and eluted with a gradient of 0-50% ethyl acetate in heptanes containing 0.1% triethylamine to give the title compound (4.4284 g, 10.03 mmol, 85% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 6.80-6.55 (m, 1H), 5.25 (s, 2H), 4.36 (td, J= 6.0, 2.8 Hz, 1H), 4.09-3.97 (m, 4H), 3.93 (dd, J= 6.1, 2.0 Hz, 2H), 3.86-3.80 (m, 2H), 3.62-3.51 (m, 2H), 3.39 (s, 3H), 2.88 (t, J= 6.7 Hz, 2H), 2.83 (s, 2H), 1.89 (t, J= 6.7 Hz, 2H), 1.45 (s, 9H); MS (ESI ⁺ ) m/z 442 [M+H] ⁺ .

Example 22G. tert-butyl [{8' - fluoro-6 ' -[(2-methoxyethoxy)methoxy]-3 ',4' - dihydro- 1'H-spiro[[1,3]dioxolane-2,2' -naphthalene]-7' - yl}({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]acetate

[00328] To a solution of chlorosulfonyl isocyanate (1.42 mL, 16.29 mmol) in dichloromethane (48 mL) at 0 °C was added allyl alcohol (1.11 mL, 16.29 mmol) dropwise such that the internal temperature remained below 10 °C. After 30 min, a previously prepared solution of the product of Example 22F (4.7953 g, 10.86 mmol) and N,N -diisopropylethylamine (3.79 mL, 21.72 mmol) in dichloromethane (24 mL) was slowly added such that the internal temperature remained below 10 °C. After 30 min, the reaction mixture was quenched with water (48 mL), stirred for 5 min, and then the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 24 mL). The combined organic layers were washed with 1 M aqueous sodium bisulfate (24 mL) and then the new aqueous layer was re-extracted with dichloromethane (15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound, which was used in the next step without purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 11.46 (s, 1H), 6.81 (s, 1H), 5.91 (ddt, J= 17.2, 10.6, 5.3 Hz, 1H), 5.37-5.28 (m, 1H), 5.25 (d, J= 7.1 Hz, 1H), 5.22 (d, J= 9.8 Hz, 1H), 5.14 (d, J = 6.8 Hz, 1H), 4.70 (d, J= 17.5 Hz, 1H), 4.63-4.48 (m, 4H), 4.08 (d, J= 17.6 Hz, 1H), 4.01-3.88 (m, 4H), 3.72 (qt, J= 11.2, 4.7 Hz, 2H), 3.46 (t, J= 4.7 Hz, 2H), 3.23 (s, 3H), 2.87 (t, J= 6.7 Hz, 2H), 2.71 (s, 2H), 1.84 (t, J= 6.6 Hz, 2H), 1.33 (s, 9H); MS (ESI ⁺ ) m/z 622 [M+NH ₄ ] ⁺ .

Example 22H. 5-{8 ' -fluoro-6 ' -[(2-methoxyethoxy)methoxy]-3 ' ,4 ' -dihydro-1 ' H-spiro[[1,3]dioxolane-2,2 ' -naphthalene]-7 ' -yl}-1 λ ^6,2,5 -thiadiazolidine-1,1,3-trione

[00329] To a solution of the product of Example 22G (6.57 g, 10.87 mmol) in methanol (117 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.251 g, 0.217 mmol). The resulting suspension was degassed with 5x vacuum/nitrogen, then sodium methoxide solution (14.9 mL, 65.2 mmol, 25 wt% in methanol) was added and the resulting suspension was heated to an internal temperature of 60 °C. After 1 h, the mixture was cooled to room temperature, diluted with ethyl acetate (66 mL), and partially concentrated to approximately 33 mL total volume to remove methanol. The resulting suspension was diluted with ethyl acetate (66 mL) and quenched with 1 M hydrochloric acid (70 mL, final pH < 3). The aqueous layer was extracted with ethyl acetate (2 x 33 mL). The combined organic layers were washed with brine (19 mL), dried over sodium sulfate, filtered through Celite® (5 g disposable frit) and concentrated in vacuo. Acetonitrile (33 mL) was added to the residue and concentrated to give the title compound (4.6781 g, 10.48 mmol, 96% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 6.83 (d, J= 1.5 Hz, 1H), 5.25 (s, 2H), 4.35 (s, 2H), 3.99-3.86 (m, 4H), 3.81-3.69 (m, 2H), 3.50-3.39 (m, 2H), 3.23 (s, 3H), 2.89 (t, J= 6.7 Hz, 2H), 2.74 (s, 2H), 1.85 (t, J= 6.6 Hz, 2H); MS (ESI ^- ) m/z 445 [MH] ^- .

Example 22I. 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthalene-2-yl}-1 λ ^6,2,5 -thiadiazolidin-1,1 ,3-trione, triethylamine salt

[00330] The product of Example 22H (2.6869 g, 6.02 mmol) was suspended in formic acid (13.4 mL, 307 mmol, 88%), quickly turning into a yellow suspension. After 15 min, the reaction mixture was diluted by slow addition of brine (54 mL). The aqueous mixture was extracted with a 2:1 mixture of ethyl acetate and acetonitrile (3 x 27 mL). The combined organic layers were washed with brine (2 x 13 mL), dried over sodium sulfate, and filtered. Triethylamine (2.52 mL, 18.06 mmol) and silica (10 g) were added to the crude solution, and the resulting suspension was concentrated in vacuo. The resulting yellow powder was dry loaded onto an 80 g silica gel column and eluted with a gradient of 0-20% methanol in dichloromethane containing 0.2% triethylamine to give the title compound (3.2400 g, 6.02 mmol, 100% yield) as a hygroscopic yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 6.93 (d, J= 1.5 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 1H), 3.80-3.71 (m, 2H), 3.50-3.41 (m, 3H), 3.23 (s, 2H), 3.17 (s, 3H), 3.02 (dd, J= 7.6, 5.9 Hz, 2H), 2.56-2.40 (m, 2H); MS (ESI ⁺ ) m/z 420 [M+NH ₄ ] ⁺ .

Example 22J: 5-{1-fluoro-3-hydroxy-7-[(4-methoxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00331] To a solution of the product from Example 22I (0.100 g, 0.186 mmol) and 4-methoxy-3,3-dimethylbutan-1-amine (0.037 g, 0.279 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.014 g, 0.223 mmol). After 3 h, a solution of HCl (0.464 mL, 1.857 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0221 g, 0.051 mmol, 27.7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.21 (br s, 1H), 8.41 (br s, 2H), 6.47 (d, J= 1.5 Hz, 1H), 3.93 (s, 2H), 3.49-3.39 (m, 2H), 3.27 (s, 3H), 3.15-3.07 (m, 1H), 3.06 (s, 2H ) ; MS (ESI ⁺ ) m/z 430 [M+H] ⁺ .

Example 23: 5-{1-fluoro-3-hydroxy-7-[(3-methoxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 122)

[00332] To a solution of the product from Example 22I (0.100 g, 0.186 mmol) and 4-methoxy-3-(3-methoxy-3-methylbutyl)amine (0.033 g, 0.279 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.014 g, 0.223 mmol). After 3 h, a solution of HCl (0.464 mL, 1.857 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0162 g, 0.039 mmol, 21% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.21 (s, 1H), 8.42 (s, 2H), 6.47 (d, J= 1.4 Hz, 1H), 3.94 (s, 2H), 3.47-3.40 (m, 1H), 3.11 (s, 3H), 3.09-3.00 (m, 2H), 2.87-2.64 (m, 2H), 2.59-2.50 (m, 1H), 2.20-2.12 (m, 1H), 1.83-1.75 (m, 2H), 1.69 (cd, J= 11.2, 5.7 Hz, 1H), 1.15 (s, 6H); MS (ESI ⁺ ) m/z 416 [M+H] ⁺ .

Example 24: 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 123)

[00333] To a solution of the product from Example 22I (0.100 g, 0.186 mmol) and 4,4,4-trifluoro-3,3-dimethylbutan-1-amine (0.043 g, 0.279 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.014 g, 0.223 mmol). After 3 h, a solution of HCl (0.464 mL, 1.857 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0200 g, 0.044 mmol, 23.8% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 9.20 (s, 1H), 8.44 (s, 2H), 6.47 (d, J= 1.3 Hz, 1H), 3.93 (s, 2H), 3.45 (s, 1H), 3.15-3.05 (m, 3H), 2.90-2.64 (m, 2H), 2.59-2.44 (m, 1H), 2.15 (t, J= 9.5 Hz, 1H), 1.81 (dd, J= 11.4, 5.9 Hz, 2H), 1.76-1.62 (m, 1H), 1.14 (s, 6H); MS (ESI ⁺ ) m/z 454 [M+H] ⁺ .

Example 25: 5-[1-fluoro-3-hydroxy-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 124)

[00334] To a solution of the product from Example 22I (0.100 g, 0.186 mmol) and 2-[1-(trifluoromethyl)cyclopropyl]ethan-1-amine hydrochloride (0.053 g, 0.279 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.014 g, 0.223 mmol). After 3 h, a solution of HCl (0.464 mL, 1.857 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0161 g, 0.036 mmol, 19.2% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 9.21 (br s, 1H), 8.44 (br s, 2H), 6.47 (d, J= 1.4 Hz, 1H), 3.93 (s, 2H), 3.50-3.39 (m, 1H), 3.16-3.02 (m, 3H), 2.86-2.64 (m, 2H), 2.57-2.51 (m, 1H), 2.17-2.09 (m, 1H), 1.91 (dd, J= 10.4, 6.5 Hz, 2H), 1.75-1.62 (m, 1H), 1.01-0.90 (m, 2H), 0.90-0.83 (m, 2H); MS (ESI ⁺ ) m/z 452 [M+H] ⁺ .

Example 26: 5-{7-[(2,2-difluoro-2-phenylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 125)

[00335] A mixture of the product of Example 22I (110 mg, 0.218 mmol), 2,2-difluoro-2-phenylethanamine, hydrochloric acid salt (85 mg, 0.437 mmol), triethylamine (66.3 mg, 0.655 mmol) and sodium cyanoborohydride (27.5 mg, 0.437 mmol) in acetonitrile (2.5 mL) was stirred at room temperature for 18 h, then 4 N HCl in dioxane (0.983 mL) was slowly added. The mixture was stirred at room temperature for 30 min and then concentrated. The resulting residue was dissolved in methanol and water (10:1 ratio, 5 mL) and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm column, 25×150 mm, flow rate 80 mL/min, 0-65% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (54 mg, 0.119 mmol, yield 54%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.04 (lat s, 1H), 7.60 (m, 2H), 7.52 (m, 3H), 6.41 (s, 1H), 3.92 (s, 2H), 3.52 (m, 2H), 3.17 (m, 1H), 2.95 (m, 1H), 2.73 (m, 1H), 2.62 (m, 1H), 2.33 (m, 1H), 2.02 (m, 1H), 1.50 (m, 1H); MS (IER-) m/z 454 [MH] ^- .

Example 27: 5-{7-[(3-cyclopropyl-2,2-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 126)

[00336] The title compound was prepared using the methodologies described in Example 26, substituting 2,2-difluoro-2-phenylethanamine hydrochloride salt for 3-cyclopropyl-2,2-difluoropropan-1-amine hydrochloride salt. ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm. 9.09 (b, s, 1H), 6.44 (s, 1H), 3.93 (s, 2H), 3.40 (m, 2H), 3.02 (m, 2H), 2.78 (m, 1H), 2.69 (m, 1H), 2.40 (m, 1H), 2.14 (m, 1H), 1.92 (m, 2H), 1.58 (m, 1H), 0.81 (m, 1H), 0.50 (m, 2H), 0.18 (m, 2H); MS (IER ^- ) m/z 432 [MH] ^- .

Example 28: 5-{1-fluoro-3-hydroxy-7-[(3-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 127)

[00337] To a solution of the product from Example 22I (0.107 g, 0.199 mmol) and 4-amino-2-methylbutan-2-ol (0.033 mL, 0.298 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.015 g, 0.238 mmol). After 19 h, a solution of HCl (0.497 mL, 1.987 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.04679 g, 0.117 mmol, 58.7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 6.41 (s, 1H), 3.94 (s, 2H), 2.93-2.56 (m, 6H), 2.21 (dd, J= 15.3, 8.1 Hz, 1H), 1.90 (dd, J= 11.9, 6.0 Hz, 1H), 1.53 (t, J= 7.2 Hz, 2H), 1.45 (dt, J= 13.4, 7.5 Hz, 1H), 1.09 (s, 6H); MS (ESI ⁺ ) m/z 402 [M+H] ⁺ .

Example 29: 5-{1-fluoro-3-hydroxy-7-[methyl(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 128)

[00338] To a solution of the product from Example 22I (0.100 g, 0.186 mmol) and methyl(3-methylbutyl)amine hydrochloride (0.038 g, 0.279 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.014 g, 0.223 mmol). After 3 h, a solution of HCl (0.464 mL, 1.857 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0106 g, 0.027 mmol, 14.3% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 9.40 (br s, 1H), 9.22 (s, 1H), 6.47 (d, J= 1.4 Hz, 1H), 3.94 (s, 2H), 3.62 (br s, 1H), 3.21-3.08 (m, 2H), 3.06-2.96 (m, 1H), 2.90-2.69 (m, 6H), 2.15 (d, J= 11.5 Hz, 1H), 1.68-1.48 (m, 3H), 0.92 (d, J= 6.3 Hz, 6H); MS (ESI ⁺ ) m/z 400 [M+H] ⁺ .

Example 30: 5-{1-fluoro-3-hydroxy-7-[(4-methylpentyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 129)

[00339] To a solution of the product from Example 22I (0.100 g, 0.186 mmol) and 4-methylpentan-1-amine (0.028 g, 0.279 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.014 g, 0.223 mmol). After 3 h, a solution of HCl (0.464 mL, 1.857 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0105 g, 0.026 mmol, 14.2% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 9.20 (s, 1H), 8.31 (br s, 2H), 6.47 (d, J= 1.4 Hz, 1H), 3.93 (s, 2H), 3.08 (dd, J= 16.0, 5.5 Hz, 1H), 3.03-2.95 (m, 2H), 2.77 (ct, J= 17.4, 8.2 Hz, 2H), 2.57-2.43 (m, 1H), 2.20-2.10 (m, 1H), 1.72-1.60 (m, 1H), 1.63-1.50 (m, 2H), 1.28-1.13 (m, 2H), 0.89 (d, J= 6.6 Hz, 6H); MS (ESI ⁺ ) m/z 400 [M+H] ⁺ .

Example 31: 5-(1-fluoro-3-hydroxy-7-{[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 130)

[00340] To a solution of the product from Example 22I (0.100 g, 0.186 mmol) and 4-amino-1,1,1-trifluoro-2-(trifluoromethyl)butan-2-ol (0.059 g, 0.0279 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.014 g, 0.223 mmol). After 3 h, a solution of HCl (0.462 mL, 1.857 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0354 g, 0.069 mmol, 37.4% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 9.19 (s, 1H), 8.43 (br s, 2H), 7.07 (br s, 1H), 6.47 (s, 1H), 3.94 (s, 2H), 3.19 (t, J= 7.8 Hz, 2H), 3.04 (dd, J= 16.2, 5.3 Hz, 1H), 2.76 (ct, J= 17.4, 5.4 Hz, 2H), 2.54-2.43 (m, 1H), 2.29-2.21 (m, 2H), 2.08 (d, J= 13.1 Hz, 1H), 1.66 (cd, J= 10.5, 5.3 Hz, 1H); MS (ESI ⁺ ) m/z 510 [M+H] ⁺ .

Example 32: 5-(1-fluoro-3-hydroxy-7-{[4,4,4-trifluoro-3-(trifluoromethyl)butyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 131)

[00341] To a solution of the product from Example 22I (0.100 g, 0.186 mmol) and 4,4,4-trifluoro-3-(trifluoromethyl)butan-1-amine hydrochloride (0.064 g, 0.279 mmol) in acetonitrile (2 mL) at room temperature was added sodium cyanoborohydride (0.014 g, 0.223 mmol). After 3 h, a solution of HCl (0.464 mL, 1.857 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 90 min, the reaction mixture was diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column, eluting with a gradient of 5-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0177 g, 0.036 mmol, 19.3% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 9.24 (s, 1H), 8.59 (br s, 2H), 6.48 (s, 1H), 4.23 (ddt, J= 11.1, 8.5, 4.5 Hz, 1H), 3.94 (s, 2H), 3.50 (s, 1H), 3.21 (t, J= 8.2 Hz, 2H), 3.06 (dd, J= 16.0, 5.4 Hz, 1H), 2.78 (kt, J= 17.4, 8.4 Hz, 2H), 2.60-2.43 (m, 1H), 2.21 -2.06 (m, 3H), 1.71 (kd, J= 10.7, 5.4 Hz, 1H); MS (ESI ⁺ ) m/z 510 [M+H] ⁺ .

Example 33: 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 132)

[00342] The title compound was prepared using the methodologies described in Example 17, substituting 2,2-difluoropropan-1-amine for 3,3,3-trifluoropropan-1-amine. ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm 9.15 (br s, 1H), 6.44 (s, 1H), 3.93 (s, 2H), 3.47 (m, 2H), 3.04 (m, 1H), 2.79 (m, 1H), 2.68 (m, 1H), 2.52 (m, 1H), 2.41 (m, 1H), 2.11 (m, 1H), 1.71 (t, J= 19 Hz, 3H), 1.59 (m, 1H); MS (IER ^- ) m/z 392 [MH] ^- .

Example 34: 5-{(7 R )-7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 133)

[00343] The product of Example 2 (100 mg, 0.261 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a CO ₂ pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical CO ₂ supplied by a dewar of bone dry non-certified CO ₂ at 350 psi with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 45% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm × 250 mm id CHIRALPAK® IC column with 5 μm particles. The peak of the later eluting enantiomer gave the title compound (26 mg, 0.068 mmol, 52% yield). ¹ H NMR and MS data were identical to those of Example 2. The absolute stereochemistry was tentatively assigned by analogy with the chromatographic elution order for the product of Example 19.

Example 35: 5-{( 7S )-7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 134)

[00344] The product of Example 2 (100 mg, 0.261 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a CO ₂ pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical CO ₂ supplied by a 350 psi dewar of bone dry non-certified CO ₂ with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 45% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm × 250 mm id CHIRALPAK® IC column with 5 μm particles. The enantiomer peak eluting early gave the title compound (25.7 mg, 0.067 mmol, 51.4% yield). ¹ H NMR and MS data were identical to those of Example 2. The absolute stereochemistry was tentatively assigned by analogy with the chromatographic elution order for the product of Example 18.

Example 36: 5-(1-fluoro-3-hydroxy-7-{[2-(pyridin-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 135)

[00345] The title compound was prepared using the methodologies described in Example 26, substituting 2-(pyridin-2-yl)ethanamine for the hydrochloride salt of 2,2-difluoro-2-phenylethanamine. ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm. 8.51 (dd, J= 6.2 Hz, 1H), 7.74 (dt, J = 2.7 Hz, 1H), 7.31 (br. d, J= 7 Hz, 1H), 7.26 (dd, J = 7.6 Hz, 1H), 6.41 (s, 1H), 3.92 (s, 2H), 3.13 (t, J= 7 Hz, 2H), 2.99 (m, 2H), 2.88 (m, 2H), 2.73 (m, 1H), 2.62 (m, 1H), 2.23 (m, 1H), 1.89 (m, 1H), 1.46 (m, 1H); MS (IER ^- ) m/z 419 [M-1] ^- .

Example 37: 5-{(7 RS )-1-fluoro-3-hydroxy-7-[(3 RS )-pyrrolidin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 136)

Example 37A: tert-butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)naphthalen-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate

[00346] To the product of Example 1G in dioxane (20 mL) were added tert -butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H- pyrrole-1-carboxylate (3.05 g, 10.32 mmol) and 1 M sodium carbonate (12.90 mL, 25.8 mmol). Tetrakis(triphenylphosphine)palladium(0) (497 mg, 0.43 mmol) was added and the reaction mixture was purged with _N2 for 5 min. The mixture was then heated at 100 °C overnight. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography (dry loading with diatomaceous earth, 5% _{CH3OH in CH2Cl2} ) to give the title compound (3.75 g, 6.77 mmol, 79% yield) as a yellow solid. ¹ H NMR (500 MHz, DMSO- d6 ) δ ppm _. 7.87-7.80 (m, 2H), 7.75 (d, J= 12.7 Hz, 1H), 7.60-7.52 (m, 2H), 7.41-7.35 (m, 3H), 7.35-7.28 (m, 1H), 6.59-6.52 (m, 1H), 5.27 (s, 2H), 4.53 (d, J= 7.7 Hz, 2H), 4.26 (d, J= 12.0 Hz, 2H), 4.09 (s, 2H), 1.47 (d, J= 10.6 Hz, 9H); MS (APCI ^- ) m/z 551 [MH] ^- .

Example 37B: tert-Butyl 3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidine-1-carboxylate

[00347] To the product of Example 37A (2.76 g, 4.99 mmol) and tetrahydrofuran (THF) (10 mL) was added 5% Pd/C (2.8 g, 12.26 mmol) in a 20 mL Parr® Barnstead Hastelloy C reactor, and the resulting mixture was stirred for 68 h under hydrogen atmosphere (61 psi) at 25°C. The volatiles were removed under reduced pressure, and the crude residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 AXIA™ (250 mm x 25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) used for 15 min at a flow rate of 25 ml/min] to give the title compound (1.7 g, 3.65 mmol, 73.3% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.74-7.67 (m, 2H), 7.44 (dd, J= 8.6, 1.7 Hz, 1H), 7.05 (d, J= 1.3 Hz, 1H), 4.10 (s, 2H), 3.75 (dd, J= 10.4, 7.5 Hz, 1H), 3.55 -3.44 (m, 2H), 3.37-3.21 (m, 2H), 2.25 (s, 1H), 2.02 (s, 1H), 1.42 (d, J= 4.3 Hz, 9H); MS (CIBP ^- ) m/z 464 [MH] ^- .

Example 37C. tert-Butyl 3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]pyrrolidine-1-carboxylate

[00348] The product of Example 37B (420 mg, 0.902 mmol) and acetic acid (9 mL) were added to 5% Pd/C (840 mg, 3.68 mmol) in a 50 mL Hastelloy C reactor, and the reaction mixture was stirred for 18 h under hydrogen (110 psi) without external heating. 10% Pd(OH) ₂ /C (420 mg, 1.495 mmol) was then added to the reactor and the hydrogenation reaction was continued under hydrogen (110 psi) for an additional 20 h at room temperature. After filtration, the volatiles were removed under reduced pressure to give the title compound, which was used in the next step without purification. MS (APCI ^- ) m / z 468 [MH] ^-

Example 37D. 5-{(7RS)-1-fluoro-3-hydroxy-7-[(3RS)-pyrrolidin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00349] The product of Example 37C (100 mg, 0.213 mmol) was dissolved in dichloromethane (DCM) (1 mL) and trifluoroacetic acid (1 mL) and stirred at ambient temperature. After 30 min, the volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® C8 (2) Luna® 5 µm AXIA™ 150 x 30 mm column eluted with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/min (0-0.5 min, 5% A, 0.5-20.5 min, linear gradient, 05-100% A, 20.7-22.7 min, 100% A, 22.7-23 min, linear gradient 100-05% A)] to afford the title compound (stereochemistry is arbitrary) and the diastereomer, Example 39. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.95 (s, 1H), 8.56 (s, 2H), 6.39 (s, 1H), 3.89 (s, 2H), 3.41-3.33 (m, 1H), 3.13-3.02 (m, 1H), 2.81 (t, J= 10.3 Hz, 1H), 2.72 (dd, J= 16.6, 5.0 Hz, 1H), 2.68-2.54 (m, 2H), 2.21-1.98 (m, 3H), 1.78 (d, J= 12.8 Hz, 1H), 1.65-1.55 (m, 3H), 1.30 (cd, J= 11.3, 5.5 Hz, 1H); MS (APCI ⁺ ) m/z 370 [M+H] ⁺ ; retention time = 14.6 minutes.

Example 38: 5-{(7 RS )-7-[(3 RS )-1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 137)

[00350] The crude product of Example 37C (100 mg, 0.213 mmol) was dissolved in dichloromethane (DCM) (1 mL) and trifluoroacetic acid (1 mL). After stirring for 30 min, the volatiles were removed under reduced pressure and the crude 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trifluoroacetate was subjected to the following reaction without purification.

[00351] To a solution of crude 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione trifluoroacetate in methylene chloride (DCM) (2 mL) was added cyclopropanesulfonyl chloride (0.055 mL, 0.541 mmol) at room temperature, followed by Hunig's base ( N,N -diisopropylethylamine) (0.142 mL, 0.812 mmol). The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure, and the crude residue was partitioned between water (5 mL) and ethyl acetate (5 mL). The organic layer was separated, the volatiles were removed under reduced pressure and the crude residue was subjected to preparative HPLC [Phenomenex® C8(2) Luna® 5 µm AXIA™ 150 x 30 mm column eluted with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/min (0-0.5 min 5% A, 0.5-20.5 min linear gradient 05-100% A, 20.7-22.7 min 100% A, 22.7-23 min linear gradient 100-05% A)] to afford the title compound (stereochemistry is arbitrary) and the diastereomer, Example 40. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.97 (s, 1H), 6.47 (s, 1H), 4.34 (s, 2H), 3.54 (dd, J= 9.6, 7.4 Hz, 1H), 3.45-3.38 (m, 1H), 3.26 (td, J= 9.7, 6.3 Hz, 1H), 3.02 (t, J= 9.5 Hz, 1H), 2.81-2.64 (m, 3H), 2.54 (s, 2H), 2.21 (dd, J= 16.5, 10.5 Hz, 1H), 2.17-2.01 (m, 2H), 1.94-1.88 (m, 1H), 1.67-1.52 (m, 2H), 1.32 (cd, J= 11.5, 5.2 Hz, 1H), 0.98-0.92 (m, 4H); MS (APCI ^- ) m/z 472 [MH] ^- ; retention time = 15.4 minutes.

Example 39: 5-{(7 RS )-1-fluoro-3-hydroxy-7-[(3 SR )-pyrrolidin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 138)

[00352] This compound was purified as described in Example 37 to give the title diastereomeric compound (stereochemistry arbitrarily assigned). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.14 (s, 1H), 8.68 (br, 1H), 8.65-8.58 (br, 1H), 6.44 (s, 1H), 3.99 (s, 2H), 3.32-3.20 (m, 2H), 3.16-3.04 (m, 1H), 2.93-2.83 (m, 1H), 2.78-2.58 (m, 3H), 2.25-2.09 (m, 3H), 1.92-1.84 (m, 1H), 1.65-1.55 (m, 2H), 1.41-1.29 (m, 1H). MS (APCI ⁺ ) m/z 370 [M+H] ⁺ ; retention time=15.8 min.

Example 40: 5-{(7 RS )-7-[(3 SR )-1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 139)

[00353] This compound was purified as described in Example 38 to give the title diastereomeric compound (stereochemistry arbitrarily assigned). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.94 (s, 1H), 6.47 (s, 1H), 4.33 (s, 2H), 3.57 (dd, J= 9.8, 7.5 Hz, 1H), 3.46-3.38 (m, 1H), 3.26 (td, J= 9.7, 6.2 Hz, 1H), 3.00 (t, J= 9.3 Hz, 1H), 2.82-2.58 (m, 4H), 2.25-2.05 (m, 1H), 2.10 (s, 2H), 1.80 (d, J= 12.8 Hz, 1H), 1.69-1.50 (m, 2H), 1.34 (tk, J= 11.3, 5.5 Hz, 1H), 1.01-0.92 (m, 4H); MS (APCI ^- ) m/z 472 [MH] ^- ; retention time = 14.8 minutes.

Example 41: 5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 140)

[00354] The crude product of Example 37C (100 mg, 0.213 mmol) was dissolved in dichloromethane (DCM) (1 mL) and trifluoroacetic acid (1 mL). After stirring for 30 min at ambient temperature, the volatiles were removed under reduced pressure and the crude 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trionetrifluoroacetate was subjected to the next reaction without purification.

Crude 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione trifluoroacetate was dissolved in N,N' -dimethylformamide (DMF) (3 mL), followed by the addition of sodium carbonate (57.4 mg, 0.541 mmol). After stirring for 5 min, cyclopropanecarbaldehyde (56.9 mg, 0.812 mmol) and acetic acid (0.077 mL, 1.354 mmol) were added, and the mixture was stirred for 5 min at room temperature. Sodium cyanoborohydride (102 mg, 1.624 mmol) was then added. The reaction mixture was stirred at ambient temperature for two hours. The mixture was then partitioned between water (5 mL) and ethyl acetate (5 mL). The aqueous layer was separated and then extracted with ethyl acetate (2 x 3 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (5 mL) and dried over sodium sulfate. The volatiles were removed under reduced pressure and the crude residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 AXIA™ (250 mm x 25 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 15 min at a flow rate of 25 mL/min] to give the title compound (22 mg, 0.052 mmol, 19% yield) as an inseparable mixture of diastereomers in a 1.7:1 ratio. MS (APCI ^- ) m/z 422 [MH] ^- .

Example 42: 5-(1-fluoro-3-hydroxy-7-{[2-(1H - pyrazol-1-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 141)

[00355] The title compound was prepared using the methodologies described in Example 26, substituting 2-( 1H- pyrazol-1-yl)ethanamine hydrochloride salt for 2,2-difluoro-2-phenylethanamine hydrochloride salt. ^1H NMR (500 MHz, DMSO -d ₆ ) δ ppm. 9.10 (s, 1H), 7.79 (d, J= 2 Hz, 1H), 7.50 (d, J= 2 Hz, 1H), 6.44 (s, 1H), 6.27 (m, 1H), 4.32 (m, 2H), 3.92 (s, 2H), 3.29 (m, 2H), 3.17 (m, 1H), 2.97 (m, 1H), 2.75 (m, 1H), 2.67 (m, 1H), 2.40 (m, 1H), 2.01 (m, 1H), 1.59 (m, 1H); MS (IER ^- ) m/z 408 [M-1] ^- .

Example 43: 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 142)

[00356] The title compound was prepared using the methodologies described in Example 1 substituting 1-bromo-3-methylbutane for 1,1,1-trifluoro-4-iodobutane. Purification by preparative HPLC [20 μm YMC TriArt™ C18 Hybrid column, 25×150 mm, 80 mL/min flow rate, gradient 0-55% CH ₃ OH in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] afforded the title compound (38 mg, 0.086 mmol, 46% yield) as the ammonium salt. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.00 (br s, 1H), 7.09 (b s, 4H), 6.42 (s, 1H), 3.93 (s, 2H), 3.73 (m, 1H), 3.53 (m, 2H), 2.84 (m, 1H), 2.74 (m, 1H), 2.62 (m, 1H), 2.45 (m, 1H), 2.27 (m, 2H), 1.88 (m, 1H), 1.72 (m, 3H); MS (IER ^- ) m/z 425 [M-1] ^- .

Example 44: 5-(8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 143)

Example 44A: N-[6-(benzyloxy)-4-bromo-2-fluoro-3-formylphenyl]-2,2,2-trifluoroacetamide

[00357] A solution of diisopropylamine (4.80 mL, 33.7 mmol) in tetrahydrofuran (21 mL) was cooled to an internal temperature of -73 °C and n -butyl lithium (14.0 mL, 33.7 mmol, 2.5 M in hexane) was added over 10 min. The mixture was stirred for 5 min, warmed to 0 °C, stirred for 10 min, and then recooled to -73 °C. A solution of N -(2-(benzyloxy)-4-bromo-6-fluorophenyl)-2,2,2-trifluoroacetamide (the compound from Example 12C) (6.00 g, 15.3 mmol) in tetrahydrofuran (41 mL) was cooled to an internal temperature of -76 °C, and a solution of lithium diisopropylamide prepared as described above was added at a rate such that the internal temperature did not exceed -70 °C. After 75 min, a solution of N,N -dimethylformamide (4.74 mL, 185 mmol) in tetrahydrofuran (15 mL) was added at a rate such that the internal temperature did not exceed -68 °C. After 20 min, the reaction was quenched with saturated aqueous ammonium chloride (30 mL), warmed to room temperature, and partitioned between ethyl acetate (2 x 50 mL) and water (50 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride solution (4 x 20 mL), dried over sodium sulfate, then filtered and concentrated under reduced pressure to give a viscous oil which was immediately purified by flash chromatography on silica gel [80 g SiO ₂ , gradient from heptanes to 30% ethyl acetate/heptanes, 60 mL/min] to give the title compound (3.58 g, 8.42 mmol, 55.6% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 11.21 (br s, 1H), 10.10 (d, J =1.1 Hz, 1H), 7.55 (d, J =1.4 Hz, 1H), 7.48-7.27 (m, 5H), 5.38 (s, 2H); MS (CIAD ⁺ ) m/z 421 [M+H] ⁺ .

Example 44B: tert-butyl {[4-(benzyloxy)-6-bromo-2-fluoro-3-(2,2,2-trifluoroacetamido)phenyl]methyl}{2-[methoxy(methyl)amino]-2- oxoethyl}carbamate

[00358] Triethylamine (4.11 mL, 29.5 mmol) was added to a solution of 2-amino- N -methoxy- N -methylacetamide hydrobromide (5.86 g, 29.5 mmol) in methanol (89 mL). After 5 min, acetic acid (0.766 mL, 13.39 mmol) was added, followed by a solution of N- [6-(benzyloxy)-4-bromo-2-fluoro-3-formylphenyl]-2,2,2-trifluoroacetamide (11.25 g, 26.8 mmol) in methanol (89 mL). After 20 min, sodium triacetoxyborohydride (11.35 g, 53.6 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 2 h. A solution of 2-amino -N -methoxy- N -methylacetamide hydrobromide (1.40 g, 7.03 mmol) and triethylamine (1.20 mL, 8.61 mmol) in methanol (15 mL) was then added, followed by sodium triacetoxyborohydride (3.00 g, 14.2 mmol). After 25 min, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 15.48 g of a viscous residue. This was dissolved in dichloromethane (179 mL) and triethylamine (4.11 mL, 29.5 mmol) was added, followed by di-tert-butyl dicarbonate (6.43 g, 29.5 mmol), and the reaction mixture was stirred at room temperature. After 14 h, water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate, then filtered and concentrated under reduced pressure to give 18.7 g of a viscous oil, which was purified by flash chromatography on silica gel [220 g SiO ₂ , heptanes → 50% ethyl acetate/heptanes, 150 mL/min] to give the title compound (12.1 g, 19.4 mmol, 72.4% yield). MS ( ^APCI ) m/z 624 [M+H] ⁺ .

Example 44C: tert-butyl 6-(benzyloxy)-8-fluoro-4-oxo-7-(2,2,2-trifluoroacetamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00359] A solution of tert -butyl {[4-(benzyloxy)-6-bromo-2-fluoro-3-(2,2,2-trifluoroacetamido)phenyl]methyl}{2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (11.0 g, 17.7 mmol) in tetrahydrofuran (142 mL) was cooled to an internal temperature of -75 °C and n -butyl lithium (15.1 mL, 36.3 mmol, 2.5 M in hexanes) was added at a rate such that the internal temperature did not exceed -70 °C. After 5 min, the reaction was quenched with saturated aqueous ammonium chloride (20 mL), warmed to room temperature, and partitioned between ethyl acetate (150 mL) and water (100 mL). The aqueous layer was re-extracted with ethyl acetate (1 x 50 mL) and the combined organic extracts were dried over sodium sulfate, then filtered and concentrated under reduced pressure to give 10.2 g of a viscous oil which was purified by flash chromatography on silica gel [120 g SiO ₂ , heptanes to 30% ethyl acetate/heptanes, 85 mL/min] to give the title compound (6.44 g, 13.4 mmol, 68.6% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 7.80 (s, 1H), 7.53 (d, J =1.5 Hz, 1H), 7.49-7.31 (m, 5H), 5.19 (s, 2H), 4.78 (s, 2H), 4.33 (s, 2H), 1.49 (s, 9H); MS (IER ^- ) m/z 481 [MH] ^- .

Example 44D: tert-butyl 6-(benzyloxy)-8-fluoro-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00360] To a solution of tert -butyl 6-(benzyloxy)-8-fluoro-4-oxo-7-(2,2,2-trifluoroacetamido)-3,4-dihydroisoquinoline-2(1 H )-carboxylate (1.50 g, 3.11 mmol) in anhydrous N,N-dimethylformamide (7.8 mL) were added 1,2,2,6,6-pentamethylpiperidine (1.13 mL, 6.22 mmol) and methyl bromoacetate (0.372 mL, 4.04 mmol), and the reaction mixture was heated to an internal temperature of 60 °C. After 1 h, the mixture was cooled to room temperature and partitioned between ethyl acetate (25 mL) and saturated aqueous ammonium chloride (20 mL). The organic layer was further washed with saturated aqueous ammonium chloride (4×20 mL), dried over sodium sulfate, then filtered and concentrated under reduced pressure to give 2.11 g of an orange oil, which was purified by flash chromatography on silica gel [24 g SiO ₂ , heptanes to 25% ethyl acetate/heptanes, 35 mL/min] to give the title compound (1.29 g, 2.33 mmol, 74.9% yield). MS (APCI ⁺ ) m/z 574 [M+NH ₄ ] ⁺ .

Example 44E: tert-butyl 6-(benzyloxy)-8-fluoro-4-[(1H-imidazol-1-carbothionyl)oxy]-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-3 ,4-dihydroisoquinoline-2(1H)-carboxylate

[00361] To a solution of tert -butyl 6-(benzyloxy)-8-fluoro-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.29 g, 2.33 mmol) in anhydrous tetrahydrofuran (23 mL) was added sodium borohydride (0.088 g, 2.33 mmol) in one portion. After 5 min, the reaction was diluted with ethyl acetate (20 mL) and quenched with saturated aqueous ammonium chloride (2 mL). The aqueous layer was re-extracted with ethyl acetate (1 x 20 mL), and the combined organic layers were dried over sodium sulfate, then filtered and concentrated under reduced pressure to give 1.26 g of an oil. The oil was dissolved in dichloromethane (23 mL) and 4-dimethylaminopyridine (0.085 g, 0.698 mmol) was added followed by 1,1'-thiocarbonyldiimidazole (0.539 g, 3.02 mmol). After 45 min, the reaction mixture was directly concentrated to give an oil, which was immediately purified by flash chromatography on silica gel [24 g SiO ₂ , heptanes to 25% acetone/heptanes, 35 mL/min, detection at 216 nm] to give the title compound (1.03 g, 1.54 mmol, 66.3% yield over two steps). MS (APCI ⁺ ) m/z 667 [M+H] ⁺ .

Example 44F. tert-butyl 6-(benzyloxy)-8-fluoro-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00362] To a solution of tert -butyl 6-(benzyloxy)-8-fluoro-4-[( 1H- imidazole-1-carbothioyl)oxy]-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-3,4-dihydroisoquinoline-2( 1H )-carboxylate (1.029 g, 1.54 mmol) and benzene (26 mL) was added tributyltin hydride (0.457 mL, 1.70 mmol). To the mixture was added a solution of triethylborane (1.70 mL, 1.70 mmol, 1.0 M in tetrahydrofuran) in one portion, and the reaction mixture was stirred at room temperature. After 8 min, the reaction mixture was concentrated to 1.5 mL and directly purified by flash chromatography on silica gel [24 g SiO ₂ , heptanes → 20% acetone/heptanes, 35 mL/min, detection at 208 nm] to give the title compound (0.705 g, 1.30 mmol, 85% yield). MS (ESI ^- ) m/z 539 [MH] ^- .

Example 44G: tert-butyl 6-(benzyloxy)-8-fluoro-7-[(2-methoxy-2-oxoethyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00363] To a solution of tert -butyl 6-(benzyloxy)-8-fluoro-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.660 g, 1.22 mmol) in anhydrous methanol (8.1 mL) was added sodium methoxide (0.70 mL, 3.05 mmol, 25% w/w in methanol) and the reaction mixture was heated to an internal temperature of 50 °C. After 2 h, the reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was partitioned between ethyl acetate (30 mL) and water (10 mL), the aqueous layer was re-extracted with ethyl acetate (2 x 5 mL), and the combined organic extracts were dried over sodium sulfate, then filtered and concentrated under reduced pressure. To remove extraneous water, the residue was dissolved in ethyl acetate (20 mL), washed with brine (1 x 10 mL), dried over sodium sulfate, then filtered and concentrated under reduced pressure. This gave 0.702 g of purified oil. The mixture was purified by flash chromatography on silica gel [12 g SiO ₂ , heptanes → 25% acetone/heptanes, 30 mL/min, detection at 208 nm] to give the title compound (0.412 g, 0.927 mmol, 71.1% yield). MS (ESI ⁺ ) m/z 445 [M+H] ⁺ .

Example 44H: tert-butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00364] To a solution of chlorosulfonyl isocyanate (0.121 mL, 1.39 mmol) in dichloromethane (4.6 mL) at an internal temperature of 0 °C was added allyl alcohol (0.095 mL, 1.39 mmol) at a rate such that the internal temperature did not exceed 7 °C. After 30 min, a previously prepared solution of tert -butyl 6-(benzyloxy)-8-fluoro-7-[(2-methoxy-2-oxoethyl)amino]-3,4-dihydroisoquinoline-2(1 H )-carboxylate (0.425 g, 0.927 mmol) and N,N -diisopropylethylamine (0.324 mL, 1.854 mmol) in dichloromethane (4.6 mL) was added at a rate such that the internal temperature did not exceed 7 °C. After 30 min, the reaction was quenched with water (48 ml) and stirred for 5 min. The layers were then separated and the aqueous layer was extracted with dichloromethane (2 x 24 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give 0.530 g of foam, which was used without purification in the next step.

[00365] A solution of the above alloc-sulfonylurea (0.473 g, 0.778 mmol) in anhydrous methanol (8.6 mL) was degassed by subsurface sparging with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.016 mmol) was then added, followed by a solution of sodium methoxide (1.07 mL, 4.67 mmol, 25% w/w in methanol) and the reaction mixture was heated to a mantle temperature of 60 °C. After 15 min, the mixture was cooled to room temperature, quenched with 1 M HCl (1 mL), and partitioned between ethyl acetate (4 mL) and water (3 mL). The aqueous layer was extracted with ethyl acetate (2×1 mL) and the combined organic extracts were washed with brine (1×5 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (314 mg, 0.639 mmol, 82% yield). MS (ESI ^- ) m/z 490 [MH] ^- .

Example 44I. 5-(8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00366] A suspension of tert -butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate (37.7 mg, 0.077 mmol) and 1,2,3,4,5-pentamethylbenzene (34.1 mg, 0.230 mmol) in dichloromethane (0.76 mL) was cooled to -78 °C, and a solution of boron trichloride (153 μL, 0.153 mmol, 1.0 M in dichloromethane) was added dropwise over 5 min. After 15 min, the reaction was quenched with anhydrous methanol (31.0 μL, 0.767 mmol) and warmed to room temperature under nitrogen. The volatiles were removed to give a solid, which was triturated with heptane (3 x 1 mL) and dichloromethane (2 x 1 mL). The crude material was then dissolved in water (2 mL), filtered through a cotton plug to remove the yellow residue, and purified by reversed-phase HPLC [Luna® 10 μM C18(2) 100 , AX (00G-4253-U0-AX), 250×30 mm, 50 mL/min, 1 injection, 5% → 95% _CH3CN / _H2O (with neat, unbuffered water) over 15 min, monitoring/collecting at 205 nm]. The product was eluted with a solvent front and then lyophilized (0.031 mbar) for 8 h to afford the title compound (9.3 mg, _0.031 mmol, 40.2% yield). ¹ H NMR (400 MHz, DMSO- d6 ) δ ppm 10.49 (br s, 1H), 9.34 (br s, 2H), 6.64 (s, 1H), 4.33 (s, 2H), 4.14 (apparent t, J = 3.8 Hz, 2H); 3.32 (apparent k, J =5.7 Hz, 2H), 2.94 (t, J =5.9 Hz, 2H); MS (IER ^- ) m/z 300 [MH] ^- .

Example 45: 5-[8-fluoro-6-hydroxy-2-(4-methylpentanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 144)

Example 45A: 5-[6-(benzyloxy)-8-fluoro-2-(4-methylpentanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00367] To a solution of tert -butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate (50 mg, 0.102 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (118 μL, 1.53 mmol). After 90 min, the reaction mixture was directly concentrated, the substrate was suspended in dichloromethane (1.0 mL), and N,N -diisopropylethylamine (71.1 μL, 0.407 mmol) was added, resulting in a homogeneous solution. Tetramethylaminium 2-( 1H- benzotriazol-1-yl)-1,1,3,3-tetrafluoroborate (TBTU) (35.9 mg, 0.112 mmol) was then added, followed by 4-methylvaleric acid (13.0 mg, 0.112 mmol), and the reaction mixture was stirred at room temperature. After 20 min, additional N,N -diisopropylethylamine (71.1 μL, 0.407 mmol) was added. After 5 min, the reaction mixture was diluted with dichloromethane (2 mL), quenched with 1 M HCl (2 mL), and extracted with dichloromethane (2×2 mL). The combined organic extracts were washed with brine (1×2 mL), dried over sodium sulfate, filtered and concentrated to give a yellow oil which was immediately purified by flash chromatography on silica gel [4 g _SiO2 , heptanes → 95% acetone/heptanes, 18 mL/min, monitor at 205 nm] to give the title compound (35.0 mg, 0.071 mmol, 69.9% yield). MS ( ^APCI ) m/z 490 [M+H] ⁺ .

Example 45B: 5-(8-fluoro-6-hydroxy-2-(4-methylpentanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[00368] A suspension of 5-[6-(benzyloxy)-8-fluoro-2-(4-methylpentanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (74.7 mg, 0.153 mmol) and 1,2,3,4,5-pentamethylbenzene (67.9 mg, 0.458 mmol) in dichloromethane (1.5 mL) was cooled to -78 °C, and a solution of boron trichloride (305 μL, 0.305 mmol, 1.0 M in dichloromethane) was added dropwise over 5 min. After 15 min, the reaction was quenched with anhydrous methanol (61.7 µL, 1.53 mmol) and warmed to room temperature under nitrogen. The volatiles were removed to give a solid, which was triturated with heptane (3 x 1 mL). The crude material was then dissolved in dimethyl sulfoxide (2 mL) and purified by reversed-phase HPLC [Luna® 10 µM C18(2) 100 , AX column (00G-4253-U0-AX), 250×30 mm, 50 mL/min, 1 injection, 5% → 95% CH ₃ CN/H ₂ O (buffer containing 29.4 g ammonium acetate in 18 L water) for 15 min, monitoring/collecting at 205 nm] to give the title compound (21.6 mg, 0.054 mmol, 35.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) (60:40 mixture of rotamers at 27°C) δ ppm 6.51 (br s, 1H), 4.51 (s, 0.8H), 4.46 (s, 1.2H), 3.94 (s, 0.8H), 3.93 (s, 1.2H), 3.63 (k, J= 5.7 Hz, 2H), 2.76 (t, J= 5.9 Hz, 1.2H) 2.64 (t, J =5.9 Hz, 0.8H), 2.38 (k, J =8.2 Hz, 2H), 1.55 (sept, J =6.8 Hz, 1H), 1.40 (m, 2H), 0.87 (d, J =6.6 Hz, 4H), 0.86 (d, J =6.6 Hz, 2H); MS (CIAD ⁺ ) m/z 400 [M+H] ⁺ .

Example 46: 5-[8-fluoro-6-hydroxy-2-(4-methylpentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 145)

[00369] To a solution of tert -butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (60 mg, 0.122 mmol) in dichloromethane (1.1 mL) was added trifluoroacetic acid (141 μL, 1.83 mmol). After 25 min, the reaction mixture was directly concentrated, suspended in acetonitrile (1.4 mL) and potassium carbonate (84 mg, 0.610 mmol) was added, then 1-bromo-4-methylpentane (40.3 mg, 0.244 mmol) and the reaction mixture was heated to 60 °C. After 16 h, the mixture was cooled to room temperature, filtered through a 0.45 μm Whatman PTFE syringe filter and the volatiles removed to leave a residue which was suspended with 1,2,3,4,5-pentamethylbenzene (46.0 mg, 0.310 mmol) in dichloromethane (1.0 mL) and cooled to -78 °C. Boron trichloride solution (207 μL, 0.207 mmol, 1.0 M in dichloromethane) was added dropwise over 5 min. After 15 min, additional boron trichloride (1.86 mL, 1.86 mmol, 1.0 M in dichloromethane) was added. After 15 min, the reaction was quenched with anhydrous ethanol (302 μL, 5.17 mmol) and warmed to room temperature under nitrogen. The volatiles were removed to give a solid which was triturated with heptane (3 x 1 mL). The crude material was then dissolved in methanol (2.5 mL) and purified by reverse phase HPLC [Luna® 10 µM C18(2) 100 , AX column (00G-4253-U0-AX), 250×30 mm, 50 mL/min, 1 injection, 5% → 95% CH ₃ CN/H ₂ O (with pure, unbuffered water) over 15 min, monitoring/collecting at 205 nm] to give the title compound (9.1 mg, 0.024 mmol, 19.7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.64 (br s, 2H), 6.58 (s, 1H), 4.28 (m, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 2.96 (m, 2H), 1.69 (pent, J = 8.0 Hz, 2H), 1.55 (sept, J = 6.8 Hz, 1H), 1.17 (q, J = 7.1 Hz, 2H), 0.86 (d, J = 6.4 Hz, 6H); MS (APCI ⁺ ) m/z 386 [M+H] ⁺ .

Example 47: 5-{(7 R )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 146)

[00370] Example 21 (76 mg, 0.179 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 delivered via a dry, non-certified _CO2 Dewar at 350 psi with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 2 mg/mL. The sample was loaded into the modifier stream in 2 mL (4 mg) injections. The mobile phase was maintained isocratically at 45% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a CHIRALPAK® IC column with a 21 mm × 250 mm i.d. and 5 μm particles. The late eluting enantiomer peak gave the title compound (21 mg, 0.049 mmol, 27.6% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.09 (br s, 1H), 6.45 (s, 1H), 3.93 (s, 2H), 3.07 (m, 4H), 2.74 (m, 2H), 2.37 (m, 2H), 2.03 (m, 1H), 1.76 (m, 2H), 1.58 (m, 2H); MS (IER ^- ) m/z 424 [MH] ^- .

Example 48: 5-{(7 S )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 147)

[00371] The title compound was prepared using the methodologies described in Example 47. The first enantiomer peak eluted to give the title compound (5 mg, 0.012 mmol, 6.6% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.18 (br s, 1H), 7.26 (br s, 1H), 6.47 (s, 1H), 3.93 (s, 2H), 3.07 (m, 4H), 2.77 (m, 2H), 2.41 (m, 2H), 2.21 (m, 1H), 1.84 (m, 2H), 1.68 (m, 2H); MS (IER ^- ) m/z 424 [MH] ^- .

Example 49: 5-[(7 R )-1-fluoro-3-hydroxy-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 148)

[00372] To a solution of the product from Example 22I (1.12 g, 2.23 mmol) and 2-[1-(trifluoromethyl)cyclopropyl]ethan-1-amine hydrochloride (0.634 g, 3.35 mmol) in acetonitrile (22 mL) at room temperature was added sodium cyanoborohydride (0.168 g, 2.68 mmol). After 18 h, the reaction mixture was quenched with ammonium hydroxide (0.506 mL, 26.8 mmol) and diluted with acetonitrile (10 mL) and water (2 mL). Celite® (5 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.1414 g, 0.262 mmol, 11.8% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 8.44 (br s, 2H), 6.77 (s, 1H), 5.21 (s, 2H), 3.98-3.86 (m, 2H), 3.77-3.70 (m, 2H), 3.50-3.42 (m, 4H), 3.23 (s, 3H), 3.17-3.09 (m, 3H), 2.86-2.76 (m, 2H), 2.58 (dd, J =16.4, 9.6 Hz, 1H), 2.16 (d, J =12.0 Hz, 1H), 1.92 (dd, J =10.4, 6.3 Hz, 2H), 1.70 (td, J =11.2, 10.4, 4.8 Hz, 2H), 1.01-0.94 (m, 2H), 0.94-0.85 (m, 3H); MS (CIAD ⁺ ) m/z 540 [M+H] ⁺ .

[00373] Earlier eluting fractions gave the alcohol by-product 5-{1-fluoro-7-hydroxy-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.303 g, 0.75 mmol, 32% yield) as the ammonium salt. MS ( ^APCI ) m / z 422 [M+NH ₄ ] ⁺ .

[00374] Racemic 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.1414 g, 0.262 mmol) was separated by chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, CO ₂ pump, modifier pump, automatic back pressure regulator (ABPR), UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 , supplied by a dewar of bone dry non-certified _CO2 at 350 psi with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 45% cosolvent: _CO2 . Fraction collection was time triggered. The instrument was equipped with a CHIRALPAK® IC column, 21 mm × 250 mm id, with 5 μm particles. The later eluting enantiomer peak gave 5-[( 7R )-1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (54.4 mg, 0.101 mmol, 77% yield). ¹ H NMR and MS were identical to those of the racemic material. The absolute configuration was assigned by analogy with the chromatographic elution order for the product of Example 19.

[00375] To a suspension of 5-[(7 R )-1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-({2-[1-(trifluoromethyl)cyclopropyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (54.4 mg, 0.101 mmol) in acetonitrile (1.1 mL) was added a solution of hydrogen chloride (0.126 mL, 0.504 mmol, 4 M in dioxane). After 2.5 h, the reaction mixture was diluted with acetonitrile (1 mL), quenched with ammonium hydroxide (0.023 mL, 1.210 mmol), and then diluted with water (0.5 mL). Celite® (1 g) was added and the resulting suspension was concentrated. The crude residue was loaded onto a 100 g C18 column and purified by reversed phase liquid chromatography, flow rate 60 ml/min, gradient 10-50% (10 column volumes) then 50-100% (6 column volumes), then wash with 100% (1 column volume) methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice), monitoring at 206 nM, to give the title compound (25.7 mg, 0.057 mmol, 57% yield). ¹ H NMR and MS were identical to the product from Example 25.

Example 50: 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl phenylcarbamate (Compound 149)

[00376] To a solution of the alcohol by-product from Example 49 5-{1-fluoro-7-hydroxy-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (50 mg, 0.118 mmol) and 4-dimethylaminopyridine (1.2 mg, 9.9 μmol) in N,N -dimethylformamide (1 mL) was added phenyl isocyanate (0.02 mL, 0.183 mmol). After 20 h, the reaction mixture was filtered through a glass fiber frit, loaded directly onto a Teledyne ISCO 50 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give 8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-ylphenylcarbamate (0.0238 g, 0.044 mmol, 45.9% yield). MS (APCI ⁺ ) m / z 541 [M + NH ₄ ] ⁺ .

[00377] To a suspension of 8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-ylphenylcarbamate (0.022 g, 0.042 mmol) in acetonitrile (0.45 mL) was added hydrogen chloride solution (0.053 mL, 0.210 mmol, 4 M in dioxane). After 1.5 h, the reaction mixture was diluted with acetonitrile (1 mL), quenched with ammonium hydroxide (0.005 mL, 0.252 mmol), and then diluted with water (0.5 mL). Celite® (1 g) was added and the resulting suspension was concentrated. The crude residue was dried on a 50 g C18 column and purified by reversed-phase liquid chromatography, flow rate 60 ml/min, gradient 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice), monitoring at 206 nM, to give the title compound (12.2 mg, 0.028 mmol, 67% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 9.65 (s, 1H), 9.11 (s, 1H), 7.46 (d, J =8.0 Hz, 2H), 7.31-7.21 (m, 2H), 6.99-6.94 (m, 2H), 6.48 (s, 1H), 5.17-5.10 (m, 1H), 4.01-3.87 (m, 2H), 3.09 (k, J =7.3 Hz, 2H), 2.93 (dd, J =16.9, 4.8 Hz, 1H), 2.89-2.64 (m, 3H); MS (HIBP ^- ) m / z 434 [MH] ^- .

Example 51: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]amino}-2,2-dimethylbutanenitrile (Compound 150)

[00378] To a solution of the product from Example 22I (0.200 g, 0.397 mmol) and 4-amino-2,2-dimethylbutanenitrile (0.074 mL, 0.596 mmol) in acetonitrile (4 mL) at room temperature was added sodium cyanoborohydride (0.030 g, 0.477 mmol). After 19 h, a solution of hydrogen chloride (0.5 mL, 1.99 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 1 h, the reaction mixture was quenched with ammonium hydroxide (0.045 mL, 2.38 mmol) and then diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice). The chromatographically purified material was further purified by trituration with acetonitrile (4 mL) to give the title compound (0.011 g, 0.027 mmol, 7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.21 (s, 1H), 6.47 (s, 1H), 3.94 (s, 2H), 3.17-3.04 (m, 3H), 2.86-2.66 (m, 3H), 2.55-2.49 (m, 1H), 2.15 (d, J = 12.3 Hz, 1H), 1.88 (dd, J =11.1, 5.8 Hz, 2H), 1.68 (tt, J =11.3, 5.6 Hz, 1H), 1.37 (s, 6H); MS (CIAD ⁺ ) m/z 411 [M+H] ⁺ .

Example 52: 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3-hydroxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 151)

[00379] To a solution of the product from Example 22I (0.20 g, 0.397 mmol) and 4-amino-1,1,1-trifluorobutan-2-ol hydrochloride (0.107 g, 0.596 mmol) in acetonitrile (4 mL) at room temperature was added sodium cyanoborohydride (0.030 g, 0.477 mmol). After 19 h, a solution of hydrogen chloride (0.496 mL, 1.99 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 1 h, the reaction mixture was quenched with ammonium hydroxide (0.045 mL, 2.38 mmol) and then diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.048 g, 0.109 mmol, 27% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 8.95 (s, 1H), 7.10 (br s, 2H), 6.41 (d, J =1.5 Hz, 1H), 4.81 (d, J =3.8 Hz, 1H), 4.21-4.09 (m, 1H), 3.93 (s, 2H), 3.93-3.84 (m, 1H), 3.57-3.43 (m, 1H), 3.13-3.02 (m, 1H), 2.76 (dt, J =17.3, 5.8 Hz, 2H), 2.67-2.51 (m, 1H), 2.35 (dd, J =16.5, 7.3 Hz, 1H), 1.80 (ddd, J =12.1, 8.6, 5.5 Hz, 1H), 2.04-1.50 (m, 3H); MS (CIAD ⁺ ) m/z 442 [M+H] ⁺ .

Example 53: 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3-methoxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 152)

[00380] To a solution of the product from Example 22I (0.20 g, 0.397 mmol) and 4,4,4-trifluoro-3-methoxybutan-1-amine (0.082 mL, 0.596 mmol) in acetonitrile (4 mL) was added sodium cyanoborohydride (0.030 g, 0.477 mmol). After 19 h, a solution of hydrogen chloride (0.496 mL, 1.99 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 1 h, the reaction mixture was quenched with ammonium hydroxide (0.045 mL, 2.383 mmol) and then diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.016 g, 0.034 mmol, 9% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.16 (s, 1H), 6.44 (d, J =1.4 Hz, 1H), 3.90 (s, 2H), 3.88 (d, J =7.3 Hz, 1H), 3.48 (s, 3H), 3.47-3.38 (m, 1H), 3.34-3.28 (m, 1H), 3.09-2.93 (m, 2H), 2.89-2.56 (m, 3H), 2.17-2.05 (m, 1H), 2.00-1.47 (m, 3H); MS (CIAD ⁺ ) m/z 456 [M+H] ⁺ .

Example 54: 5-[8-fluoro-6-hydroxy-2-(5,5,5-trifluoropentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 153)

Example 54A: 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate

[00381] Trifluoroacetic acid (0.1 mL, 1.34 mmol, 15.0 equivalents) was added to a suspension of tert -butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate, the product of Example 44H (44 mg, 0.09 mmol, 1 equivalent), in dichloromethane (0.45 mL) at 23 °C. The reaction mixture was stirred for 30 min at 23 °C. The product mixture was then diluted with ether (1.0 mL) at 23 °C. A precipitate formed immediately. The diluted mixture was concentrated under a stream of nitrogen. The resulting title compound was used without further purification. MS (CIAD ⁺ ) m / z 433 [M+H+CH ₃ CN] ⁺ .

Example 54B: 5-[6-(benzyloxy)-8-fluoro-2-(5,5,5-trifluoropentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00382] A suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate, the product of Example 54A (nominally 0.09 mmol, 1 equivalent), potassium carbonate (62 mg, 0.45 mmol, 5.0 equivalent), and 5,5,5-trifluoropentyl 4-methylbenzenesulfonate (40 mg, 0.14 mmol, 1.5 equivalents; Erdeljac, N., et al. Chem. Commun , 2018, 54 , 12002-12005) in acetonitrile (0.45 mL) was heated to 60 °C with stirring for 19 h. The reaction mixture was then cooled to 23°C. The cooled reaction mixture was successively diluted with aqueous hydrogen chloride (1.0 M, 0.5 mL), water (0.5 mL), and dimethyl sulfoxide (1.0 mL). The diluted mixture was purified by reverse-phase flash column chromatography (100 g RediSep Rf ^Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min). The resulting title compound (44 mg) was used in the next step without further purification. MS (CIBP ⁺ ) m / z 516 [M+H] ⁺ .

Example 54C: 5-[8-fluoro-6-hydroxy-2-(5,5,5-trifluoropentyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00383] A solution of boron trichloride in dichloromethane (1.0 M, 0.9 mL, 0.90 mmol, 11.3 equivalents) was added to a suspension of the product of Example 54B (nominal 44 mg, 0.08 mmol, 1 equivalent) and pentamethylbenzene (37 mg, 0.25 mmol, 3.0 equivalents) in dichloromethane (0.85 mL) at -78 °C. The reaction mixture was stirred for 4 hours at -78 °C. The reaction mixture was then diluted with methanol (0.5 mL) at -78 °C. The diluted mixture was warmed to 23 °C for 15 minutes. The heated mixture was concentrated. The resulting residue was purified by reverse phase flash column chromatography (100 g RediSep Rf Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min) to give the title compound (14 mg, 41% yield, two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.52 (s, 1H), 4.10 (k, J =5.2 Hz, 1H), 3.94 (2, 2H), 3.17 (d, J =5.1 Hz, 2H), 2.86 (ap. lat., 2H), 2.35-2.23 (m, 2H), 1.71 (ap. lat., 2H), 1.59-1.47; MS (CIBP ⁺ ) m / z 426 [M+H] ⁺ .

Example 55: 5-(1-fluoro-3-hydroxy-7-{(3-methylbutyl)[(pyridin-2-yl)methyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 154)

[00384] To a solution of the product from Example 22I (0.3492 g, 0.693 mmol) and 2-(aminomethyl)pyridine (0.192 mL, 1.66 mmol) in acetonitrile (7 mL) at room temperature was added sodium cyanoborohydride (0.087 g, 1.39 mmol). After 19 h, isovaleraldehyde (0.299 mL, 2.77 mmol) was added. After 6 h, a solution of hydrogen chloride (1.73 mL, 6.93 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 1 h, the reaction mixture was quenched with ammonium hydroxide (0.157 mL, 8.32 mmol) and then diluted with acetonitrile (4 mL) and water (2 mL). Celite® (2 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice). The eluting fractions were later combined and concentrated to give the title compound (0.163 g, 0.341 mmol, 49% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.21 (s, 1H), 8.66 (d, J =5.2 Hz, 1H), 7.92 (td, J =7.7, 1.9 Hz, 1H), 7.58 (d, J =7.8 Hz, 1H), 7.49-7.41 (m, 1H), 6.46 (s, 1H), 4.64-4.46 (m, 2H), 3.93 (s, 2H), 3.75-3.58 (m, 1H), 3.49-3.40 (m, 1H), 3.27-3.06 (m, 3H), 2.90-2.68 (m, 4H), 1.86-1.77 (m, 1H), 1.59-1.41 (m, 3H), 0.83 (d, J =2.2 Hz, 3H), 0.81 (d, J =2.2 Hz, 3H); MS (CIAD ⁺ ) m/z 477 [M+H] ⁺ .

Example 56: 5-(1-fluoro-3-hydroxy-7-{[(pyridin-2-yl)methyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 155)

[00385] To a solution of the product from Example 22I (0.3492 g, 0.693 mmol) and 2-(aminomethyl)pyridine (0.192 mL, 1.66 mmol) in acetonitrile (7 mL) at room temperature was added sodium cyanoborohydride (0.087 g, 1.387 mmol). After 19 h, isovaleraldehyde (0.299 mL, 2.77 mmol) was added. After 6 h, a solution of hydrogen chloride (1.73 mL, 6.93 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 1 h, the reaction mixture was quenched with ammonium hydroxide (0.157 mL, 8.32 mmol) and then diluted with acetonitrile (4 mL) and water (2 mL). Celite® (2 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice). The fractions eluted previously were combined and concentrated to give the title compound (0.0972 g, 0.239 mmol, 34.5% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) showed a mixture of rotamers, the major rotamer being δ ppm. 9.37 (s, 1H), 9.21 (s, 2H), 8.57 (td, J =5.0, 1.7 Hz, 1H), 7.84 (td, J =7.7, 1.8 Hz, 1H), 7.49-7.41 (m, 1H), 7.35 (dt, J =8.0, 4.2 Hz, 1H), 6.43 (s, 1H), 5.03-4.87 (m, 2H), 4.38-4.24 (m, 1H), 4.00-3.78 (m, 2H), 3.45 (dd, J =5.9, 3.7 Hz, 1H), 3.00-2.53 (m, 3H), 2.33 (s, 2H), 1.89-1.62 (m, 2H); MS (CIAD ⁺ ) m/z 477 [M+H] ⁺ .

Example 57: 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-2-hydroxybutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 156)

[00386] To a solution of the product from Example 22I (0.302 g, 0.600 mmol) and 1-amino-4,4,4-trifluorobutan-2-ol (0.1 g, 0.699 mmol) in acetonitrile (6 mL) was added sodium cyanoborohydride (0.045 g, 0.715 mmol). After 18 h, a solution of hydrogen chloride (1.19 mL, 4.77 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 2 h, the reaction mixture was quenched with ammonium hydroxide (0.068 mL, 3.57 mmol) and then diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0694 g, 0.157 mmol, 26.4% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.26 (s, 1H), 8.65 (br s, 2H), 6.46 (s, 1H), 5.84 (s, 1H), 4.15 (s, 1H), 4.12-4.08 (m, 1H), 3.94 (d, J = 1.2 Hz, 2H), 3.50-3.39 (m, 1H), 3.22-3.17 (m, 1H), 3.15-2.99 (m, 2H), 2.86-2.67 (m, 2H), 2.64-2.41 (m, 2H), 2.23-2.12 (m, 1H), 1.79-1.62 (m, 1H); MS (CIAD ⁺ ) m/z 442 [M+H] ⁺ .

Example 58: 5-(7-{[2-(difluoromethoxy)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 157)

[00387] To a solution of the product from Example 22I (0.302 g, 0.600 mmol) and 2-(difluoromethoxy)ethan-1-amine (0.1 g, 0.900 mmol) in acetonitrile (6 mL) was added sodium cyanoborohydride (0.045 g, 0.715 mmol) at room temperature. After 18 h, a solution of hydrogen chloride (1.191 mL, 4.77 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 2 h, the reaction mixture was quenched with ammonium hydroxide (0.068 mL, 3.57 mmol) and then diluted with acetonitrile (3 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0604 g, 0.148 mmol, 24.6% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.29 (s, 1H), 8.79 (br s, 2H), 6.80 (t, J =75.2 Hz, 1H), 6.48 (d, J =1.3 Hz, 1H), 4.17-4.08 (m, 2H), 3.96 (d, J =2.1 Hz, 2H), 3.52-3.44 (m, 1H), 3.39 (t, J =5.2 Hz, 2H), 3.16-3.08 (m, 1H), 2.83 (dt, J =17.2, 4.6 Hz, 1H), 2.75 (ddd, J =17.0, 11.4, 5.4 Hz, 1H), 2.61-2.53 (m, 1H), 2.23-2.16 (m, 1H), 1.72 (cd, J =11.7, 5.4 Hz, 1H); MS (CIAD ⁺ ) m/z 410 [M+H] ⁺ .

Example 59: 5-(8-fluoro-6-hydroxy-2-pentanimidoyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 158)

Example 59A: 5-[6-(benzyloxy)-8-fluoro-2-pentanimidoyl-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00388] N,N -diisopropylethylamine (0.15 mL, 0.84 mmol, 5.5 equivalents) was added to a suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate, the product of Example 54A (nominally 0.15 mmol, 1 equivalent) and ethyl pentanimidate hydrochloride (50 mg, 0.31 mmol, 2.0 equivalents; Goebel, M, et al. ChemMedChem 2009, 4, 1136-1142) in acetonitrile (0.75 mL) at 23°C. The reaction vessel was sealed and the sealed vessel was placed in a heating block preheated to 60 °C. The reaction mixture was stirred for 18 h at 60 °C. Then, the reaction mixture was cooled to 23 °C. Additional ethyl pentanimidate hydrochloride (150 mg, 0.93 mmol, 6.0 equivalents) and N,N -diisopropylethylamine (0.40 mL, 2.29 mmol, 15.0 equivalents) were added at 23 °C. The reaction vessel was sealed and the sealed vessel was placed in a heating block preheated to 60 °C. The reaction mixture was stirred for 3 h at 60 °C and then cooled to 23 °C. The cooled mixture was diluted successively with aqueous hydrogen chloride (1.0 M, 3.0 mL) and dimethyl sulfoxide (3.0 mL). The diluted mixture was purified by reverse-phase flash column chromatography (100 g RediSep Rf Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min). The title compound (146 mg) was used in the next step without further purification. MS (APCI ⁺ ) m / z 475 [M+H] ⁺ .

Example 59B: 5-(8-fluoro-6-hydroxy-2-pentanimidoyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00389] A solution of boron trichloride in dichloromethane (1.0 M, 0.31 mL, 0.31 mmol, 1.0 equivalent) was added to a suspension of pentamethylbenzene (141 mg, 0.92 mmol, 3.0 equivalent) and the product of Example 59A (nominal 146 mg, 0.307 mmol, 1 equivalent) in dichloromethane (3.0 mL) at -78 °C. The reaction mixture was stirred for 15 min at -78 °C. An additional solution of boron trichloride in dichloromethane (1.0 M, 0.35 mL, 0.35 mmol, 1.17 equivalent) was added at -78 °C. The reaction mixture was stirred for 30 min at -78 °C. An additional solution of boron trichloride in dichloromethane (1.0 M, 0.40 mL, 0.40 mmol, 1.33 equivalents) was added at -78 °C. The reaction mixture was stirred for 30 min at -78 °C. The mixture was then successively diluted with ethyl acetate (1.5 mL) and ethanol (1.5 mL) at 78 °C. The diluted mixture was heated to 23 °C for 15 min. The heated mixture was concentrated. The resulting residue was purified by reverse phase flash column chromatography (100 g RediSep Rf Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min) to give the title compound (12 mg, 0.031 mmol, 10% yield, two steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 6.47 (s, 1H), 4.51 (s, 2H), 4.19 (d, J =17.5 Hz, 1H), 3.75-3.61 (m, 2H), 3.23 (d, J =17.5 Hz, 1H), 2.82 (t, J =5.9 Hz, 2H), 2.58 (t, J =7.9 Hz, 2H), 1.56-1.48 (m, 2H), 1.41-1.31 (m, 2H), 0.91 (t, J =7.9 Hz, 2H); MS (CIBP ⁺ ) m / z 385 [M+H] ⁺ .

Example 60: 5-[2-(3-cyclopropylpropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 159)

Example 60A: 5-[6-(benzyloxy)-2-(3-cyclopropylpropyl)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ6,2,5 ^- thiadiazolidin-1 ,1,3-trione

[00390] A suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate, the product of Example 54A (nominally 0.15 mmol, 1 equivalent), potassium carbonate (106 mg, 0.77 mmol, 5.0 equivalent), and 3-cyclopropylpropyl 4-methylbenzenesulfonate (60 mg, 0.23 mmol, 1.5 equivalents; Wagner, PJ, et al. J. Am. Chem. Soc. 1981, 103, 3837-3841) in acetonitrile (0.80 mL) was sealed in a 4 mL vial. The sealed vessel was placed in a heating block preheated to 60 °C. The reaction mixture was stirred for 18 h at 60 °C. Then the reaction mixture was cooled to 23 °C. The cooled mixture was diluted with dimethyl sulfoxide (3.0 mL). The diluted mixture was purified by reverse phase flash column chromatography (100 g RediSep Rf Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min) to afford the title compound (68 mg, 0.14 mmol, 93% yield, two steps). MS (CIBP ⁺ ) m / z 474 [M+H] ⁺ .

Example 60B: 5-[2-(3-cyclopropylpropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00391] To a solution of boron trichloride in dichloromethane (1.0 M, 0.14 mL, 0.14 mmol, 1.0 equivalent) was added a suspension of the product of Example 60A (65 mg, 0.14 mmol, 1 equivalent) and pentamethylbenzene (61 mg, 0.41 mmol, 3.0 equivalents) in dichloromethane (1.4 mL) at -78 °C. The reaction mixture was stirred for 15 min at -78 °C. An additional solution of boron trichloride in dichloromethane (1.0 M, 0.30 mL, 0.30 mmol, 2.1 equivalents) was added at -78 °C. The reaction mixture was stirred for 15 min at -78 °C and then diluted with methanol (0.5 mL) at -78 °C. The diluted mixture was heated to 23°C for 15 min. The heated product mixture was concentrated. The resulting residue was purified by reverse phase flash column chromatography (100 g RediSep Rf Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min). Fractions containing the product were combined and the combined fractions were concentrated. The resulting residue was re-purified under the same chromatographic conditions to afford the title compound (5 mg, 0.013 mmol, 9% yield). ¹ H NMR (500 MHz, DMSO _-d6 ) δ ppm 6.33 (s, 1H), 3.95 (s, 2H), 2.69-2.62 (m, 2H), 2.59-2.54 (m, 2H), 2.49-2.44 (m, 2H), 1.59 (p, J =7.4 Hz, 2H), 1.24-1.13 (m, 4H), 0.74-0.65 (m, 1H), 0.40-0.36 (m, 2H), 0.02- -0.01 (m, 2H). MS (CIBP ⁺ ) m / z 384 [M+H] ⁺ .

Example 61: 5-[2-(2-azaspiro[3.3]heptan-6-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 160)

Example 61A: 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00392] A vial containing a suspension of tert -butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.200 g, 0.407 mmol, Example 44H) in dichloromethane (1.4 mL) was cooled to 0 °C. 2,2,2-Trifluoroacetic acid (0.19 mL, 2.4 mmol) was then added dropwise and the cooling bath was subsequently removed. After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (3×3 mL) and then passed through an SCX-2 cartridge (loaded and eluted first with methanol/dichloromethane (1:1) and then eluted with 2 M ammonia in methanol) to give the title compound (0.159 g, 0.406 mmol, 100% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.49 (dd, J = 7.0, 1.6 Hz, 2H), 7.38-7.32 (m, 2H), 7.32-7.27 (m, 1H), 6.86 (s, 1H), 5.15 (s, 2H), 4.18 (s, 2H), 3.96 (s, 2H), 3.36-3.31 (m, 2H), 2.94 (t, J = 6.2 Hz, 2H); MS (ESI ⁺ ) m/z 433.2 [M+CH ₃ CN+H] ⁺ ; MS (ESI ^- ) m/z 390.2 [MH] ^- .

Example 61B: tert-butyl 6-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-azaspiro[3.3]heptane-2-carboxylate

[00393] To the vial were added 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.040 g, 0.10 mmol, Example 61A), tert -butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (0.024 g, 0.11 mmol), and dichloromethane (0.34 mL). The resulting suspension was stirred at ambient temperature for 10 min, then sodium triacetoxyhydroborate (0.043 g, 0.20 mmol) was added. After 16 h, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and stirred for 20 min. Water was then added and the mixture was extracted with dichloromethane (4 x 20 mL). The organic phases were combined, washed successively with 50% aqueous sodium chloride and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound. This material was used without further purification. MS (ESI ⁺ ) m/z 587.0 [M+H] ⁺ ; MS ( ^ESI- ) m/z 585.2 [MH] ^- .

Example 61C: tert-butyl 6-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-azaspiro[3.3]heptane-2-carboxylate

[00394] To a 20 mL Barnstead Hast C reactor containing 5% palladium on carbon (0.120 g, 0.525 mmol) were added tert -butyl 6-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]-2-azaspiro[3.3]heptane-2-carboxylate (theoretical 0.10 mmol, Example 61B) and tetrahydrofuran (2 mL). The resulting mixture was stirred at ambient temperature for 2.7 h under a hydrogen atmosphere at 50 psi. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (0.033 g, 0.066 mmol). This material was used without further purification. MS (ESI ⁺ ) m/z 497.2 [M+H] ⁺ ; MS ( ^ESI- ) m/z 495.2 [MH] ^- .

Example 61D: 5-[2-(2-azaspiro[3.3]heptan-6-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00395] A vial containing a suspension of tert -butyl 6-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2( 1H )-yl]-2-azaspiro[3.3]heptane-2-carboxylate (0.033 g, 0.066 mmol, Example 61C) in dichloromethane (0.22 mL) was cooled to 0 °C. 2,2,2-Trifluoroacetic acid (0.031 mL, 0.40 mmol) was then added dropwise, after which the cooling bath was removed. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (3×3 mL) and purified using reversed-phase preparative HPLC [Waters XBridge™ RP18, 5 μm, 30×100 mm column, flow rate 40 mL/min, gradient of 5-70% methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)]. Fractions containing the product were combined and concentrated under reduced pressure. The residue was passed through an SCX-2 cartridge (loaded and eluted first with methanol/dichloromethane (1:1), then eluted with 2 M ammonia in methanol) to afford the title compound (5.0 mg, 0.013 mmol, 13% yield over three steps). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 6.44 (s, 1H), 3.98 (s, 2H), 3.94 (s, 2H), 3.87 (s, 2H), 3.28 (s, 2H), 2.76 (p, J =7.6 Hz, 1H), 2.67 (t, J =5.8 Hz, 2H), 2.49-2.40 (m, 2H), 2.43-2.36 (m, 1H), 2.14-1.95 (m, 2H); MS (ESI ⁺ ) m/z 397.2 [M+H] ⁺ .

Example 62: 5-[8-fluoro-6-hydroxy-2-(6,6,6-trifluorohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 161)

Example 62A: 5-[6-(benzyloxy)-8-fluoro-2-(6,6,6-trifluorohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00396] A suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate, the product of Example 54A (nominally 0.25 mmol, 1 equivalent), triethylamine (0.18 mL, 1.3 mmol, 5.0 equivalent), and 6-bromo-1,1,1-trifluorohexane (86 mg, 0.38 mmol, 1.5 equivalents) in acetonitrile (1.3 mL) was sealed in a 4 mL vial. The sealed vial was placed on a heating block preheated to 60 °C. The reaction mixture was stirred at 60 °C for 18 h and then cooled to 23 °C. The cooled mixture was concentrated. The resulting residue was purified by reverse-phase flash column chromatography (100 g RediSep Rf Gold ^® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min) to afford the title compound (53 mg, 0.10 mmol, 39% yield). MS (APCI ⁺ ) m / z 530 [M+H] ⁺ .

Example 62B: 5-[8-fluoro-6-hydroxy-2-(6,6,6-trifluorohexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00397] To a suspension of the product of Example 62A (53 mg, 0.10 mmol, 1 equivalent) and pentamethylbenzene was added a solution of boron trichloride in dichloromethane (1.0 M, 1.0 mL, 1.0 mmol, 10.0 equivalents) slowly down the side of the flask. (48 mg, 0.33 mmol, 3.3 equivalents) in dichloromethane (1.5 mL) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C and then slowly diluted with ethanol (0.8 mL) at -78 °C. The diluted mixture was warmed to 23 °C over 30 min and concentrated. The resulting residue was triturated with heptanes (3 x 5 mL). The resulting residue was purified by reverse phase flash column chromatography (100 g RediSep Rf Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol over 3 column volumes, flow rate = 60 mL/min) to afford the title compound (8.6 mg, 20% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.59 (br, 1H), 6.55 (s, 1H), 3.94 (s, 2H), 3.25-2.83 (m, 6H), 2.34-2.20 (m, 2H), 1.76-1.66 (m, 2H), 1.53 (p, J = 7.2 Hz, 2H), 1.39 (p, J = 7.7 Hz, 2H). MS (APCI ⁺ ) m / z 440 [M+H] ⁺ .

Example 63: 5-{2-[(3,3-difluorocyclobutyl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 162)

Example 63A: 5-{6-(benzyloxy)-2-[(3,3-difluorocyclobutyl)methyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1 λ ⁶ .2, 5-thiadiazolidine-1,1,3-trione

[00398] A suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate, the product of Example 54A (nominally 0.25 mmol, 1 equivalent), potassium carbonate (176 mg, 1.27 mmol, 5.0 equivalents), and 3-(bromomethyl)-1,1-difluorocyclobutane (61 mg, 0.33 mmol, 1.3 equivalents) in acetonitrile (1.3 mL) was sealed in a 4 mL vial. The sealed vial was placed on a heating block preheated to 60°C. The reaction mixture was stirred for 18 h at 60 °C and then cooled to 23 °C. The cooled mixture was filtered through a pad of diatomaceous earth (1.0 cm × 0.5 cm). The filter cake was washed with acetonitrile (5 × 1.0 mL). The filtrates were combined and the combined filtrates were passed through a ^Whatman® syringe filter with a 0.45 μm PTFE membrane. The filtrate was concentrated. The resulting residue was used without further purification in the next step. MS (APCI ⁺ ) m / z 496 [M+H] ⁺ .

Example 63B: 5-{2-[(3,3-difluorocyclobutyl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00399] A solution of boron trichloride in dichloromethane (1.0 M, 2.0 mL, 2.0 mmol, 7.9 equivalents) was slowly added down the side of the flask to a suspension of the product of Example 63A (nominally 0.25 mmol, 1 equivalent) and pentamethylbenzene (122 mg, 0.92 mmol, 3.3 equivalents) in dichloromethane (2.0 mL) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C and then slowly diluted with ethanol (0.8 mL) at -78 °C. The diluted mixture was warmed to 23 °C over 30 min and concentrated. The resulting residue was triturated with heptanes (3 x 5 mL). The resulting residue was purified by reverse phase flash column chromatography (100 g RediSep Rf Gold ^® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min) to give the title compound (8 mg, 0.020 mmol, 8% yield, three steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.71 (br, 1H), 6.58 (s, 1H), 4.52-4.08 (m, 2H), 3.96 (s, 2H), 3.11-2.63 (m, 6H); MS (APCI ⁺ ) m / z 406 [M+H] ⁺ .

Example 64: 5-[2-(azetidin-3-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 163)

Example 64A: tert-butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]azetidine-1-carboxylate

[00400] 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.045 g, 0.12 mmol, Example 61A), tert -butyl 3-oxoazetidine-1-carboxylate (0.022 g, 0.13 mmol), and dichloromethane (0.38 mL) were added to the vial. The suspension was stirred at ambient temperature for 10 min, then sodium triacetoxyhydroborate (0.049 g, 0.23 mmol) was added. After 14 h, additional tert -butyl 3-oxoazetidine-1-carboxylate (0.022 g, 0.13 mmol) and sodium triacetoxyhydroborate (0.049 g, 0.23 mmol) were added. After an additional 4 h, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and stirred for 20 min. Water was then added and the mixture was extracted with dichloromethane (4 x 20 mL). The organic phases were combined, washed successively with 50% aqueous sodium chloride and brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. This material was used without further purification. MS (ESI ⁺ ) m/z 588.1 [M+ _CH3CN +H] ⁺ ; MS ( ^ESI- ) m/z 545.2 [MH] ^- .

Example 64B: tert-butyl 3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]azetidine-1-carboxylate

[00401] To a 20 mL Barnstead Hast C reactor containing 5% palladium on carbon (0.057 g, 0.25 mmol) were added tert -butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]azetidine-1-carboxylate (theoretical 0.12 mmol, Example 64A) and tetrahydrofuran (2 mL). The resulting mixture was stirred at ambient temperature for 1.8 h under a hydrogen atmosphere at 100 psi. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and purified by preparative reverse phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/min, 5-70% gradient of acetonitrile in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (0.019 g, 0.042 mmol, 36% yield over two steps). ¹ H NMR (500 MHz, methanol -d ₄ ) δ ppm 7.26 (d, J =1.3 Hz, 1H), 4.76 (s, 2H), 4.71 (s, 2H), 4.16 (s, 2H), 4.10 (s, 1H), 3.51 (t, J =5.9 Hz, 2H), 3.37-3.30 (m, 4H), 2.15 (s, 9H); MS (ESI ⁺ ) m/z 456.9 [M+H] ⁺ .

Example 64C: 5-[2-(azetidin-3-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00402] A vial containing a solution of tert -butyl 3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2( 1H )-yl]azetidine-1-carboxylate (0.019 g, 0.042 mmol, Example 64B) in dichloromethane (0.21 mL) was cooled to 0 °C. 2,2,2-trifluoroacetic acid (0.019 mL, 0.25 mmol) was then added dropwise and the resulting mixture was stirred at 0 °C. After 1 h, more 2,2,2-trifluoroacetic acid (0.019 mL, 0.25 mmol) was added and the cooling bath was removed. After another 1.5 h, the reaction mixture was passed through an SCX-2 cartridge (loaded and eluted first with methanol/dichloromethane (1:1) and then eluted with 2 M ammonia in methanol) to give the title compound (5.5 mg, 0.015 mmol, 37% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 8.78 (s, 3H), 6.47 (d, J =1.3 Hz, 1H), 4.04 (dd, J =10.9, 7.3 Hz, 2H), 3.97-3.89 (m, 4H), 3.48 (p, J =7.0 Hz, 1H), 3.41 (s, 2H), 2.73 (t, J =5.9 Hz, 2H), 2.55 (t, J =5.8 Hz, 2H); MS (CIAD ⁺ ) m/z 357.4 [M+H] ⁺ .

Example 65: 5-(8-fluoro-6-hydroxy-2-{2-[(propan-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 164)

Example 65A: 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00403] To a solution of the product of Example 44H (133 mg, 0.271 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (617 mg, 5.41 mmol). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give the title compound as a trifluoroacetic acid salt (137 mg, 0.271 mmol, 100% yield). MS (ESI ^- ) m/z 390 [MH] ^- .

Example 65B: tert-Butyl {2-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}propan-2-ylcarbamate

[00404] A mixture of the product of Example 65A (138 mg, 0.274 mmol), triethylamine (139 mg, 1.370 mmol), tert- butyl isopropyl (2-oxoethyl)carbamate (60.7 mg, 0.301 mmol), and sodium triacetoxyborohydride (232 mg, 1.096 mmol) in acetonitrile and methanol (4:1, 1.5 mL) was stirred at room temperature for 1.5 h. The mixture was quenched with methanol/water (1:2, 2 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm, 25×150 mm column, flow rate 80 mL/min, 0-80% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (79 mg, 0.137 mmol, yield 50%). MS (ESI ^- ) m/z 575 [MH] ^- .

Example 65C: 5-[6-(benzyloxy)-8-fluoro-2-{2-[(propan-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00405] To a solution of the product of Example 65B (73 mg, 0.127 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (722 mg, 6.33 mmol). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give the title compound (75 mg, 0.127 mmol, 100% yield) as a trifluoroacetic acid salt. MS (ESI ^- ) m/z 475 [MH] ^- .

Example 65D: 5-(8-fluoro-6-hydroxy-2-{2-[(propan-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00406] To a mixture of 1,2,3,4,5-pentamethylbenzene (55.0 mg, 0.371 mmol) and the product of Example 65C (73 mg, 0.124 mmol) in dichloromethane (3 mL) at -78 °C was added trichloroborane (1.48 mL, 1.48 mmol, 1 M in dichloromethane). The mixture was stirred at -78 °C for 10 min, then at 20 °C for 20 min. The mixture was quenched with ethanol (2 mL) and concentrated under reduced pressure. The residue was washed with heptane (4 x 4 mL) and dichloromethane (6 x 3 mL) and dried under reduced pressure to give the title compound (33 mg, 0.066 mmol, 53% yield). ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm 11.16 (br s, 1H), 10.40 (br s, 1H), 9.10 (br s, 2H), 6.65 (s, 1H), 4.30-4.60 (m, 2H), 4.27 (s, 2H), 3.40-3.54 (m, 4H), 3.15-3.30 (m, 4H), 3.07 (m, 1H), 1.28 (d, J = 7 Hz, 6H); MS (ESI ^- ) m/z 385 [MH] ^- .

Example 66: 5-{2-[(azetidin-3-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 165)

Example 66A: tert-butyl 3-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}azetidine-1-carboxylate

[00407] To the vial were added 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.045 g, 0.12 mmol, Example 61A), tert -butyl 3-formyl azetidine-1-carboxylate (0.023 g, 0.13 mmol), and dichloromethane (0.38 mL). The suspension was stirred at ambient temperature for 10 min, then sodium triacetoxyhydroborate (0.049 g, 0.23 mmol) was added. After 14 h, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and stirred for 20 min. Water was then added and the mixture was extracted with dichloromethane (4 x 20 mL). The organic phases were combined, washed successively with 50% aqueous sodium chloride and brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound. This material was used without further purification. MS (ESI ⁺ ) m/z 561.1 [M+H] ⁺ .

Example 66B: tert-Butyl 3-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}azetidine-1-carboxylate

[00408] To a 20 mL Barnstead Hast C reactor containing 5% palladium on carbon (0.067 g, 0.29 mmol) were added tert -butyl 3-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]methyl}azetidine-1-carboxylate (theoretical 0.12 mmol, Example 66A) and tetrahydrofuran (2 mL). The resulting mixture was stirred at ambient temperature for 2.4 h under 100 psi of hydrogen. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and purified by preparative reverse phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/min, 5-70% gradient of acetonitrile in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (0.023 g, 0.049 mmol, 43% yield over two steps). ¹ H NMR (500 MHz, methanol -d ₄ ) δ ppm 6.60-6.56 (m, 1H), 4.22 (s, 2H), 4.10 (t, J = 8.5 Hz, 2H), 3.97 (s, 2H), 3.71 (d, J = 8.4 Hz, 2H), 3.24 (d, J = 7.3 Hz, 2H), 3.19-3.13 (m, 2H), 3.11-3.02 (m, 1H), 2.99 (t, J = 6.1 Hz, 2H), 1.43 (s, 9H); MS (ESI ⁺ ) m/z 471.1 [M+H] ⁺ ; MS (ESI ^- ) m/z 469.1 [MH] ^- .

Example 66C: 5-{2-[(azetidin-3-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00409] A vial containing a suspension of tert -butyl 3-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2( 1H )-yl]methyl}azetidine-1-carboxylate (0.023 g, 0.049 mmol, Example 66B) in acetonitrile (0.24 mL) was cooled to 0°C. A solution of hydrogen chloride (2.0 M in diethyl ether, 0.098 mL, 0.20 mmol) was added dropwise, after which the cooling bath was removed. After 1 h, a second portion of hydrogen chloride (2.0 M in diethyl ether, 0.098 mL, 0.20 mmol) was added along with a few drops of water. After an additional 2.5 h, the mixture was concentrated under reduced pressure and purified by reversed-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30 x 100 mm, flow rate 40 mL/min, 5-70% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)]. Fractions containing the product were combined and concentrated under reduced pressure. The residue was passed through an SCX-2 cartridge (loaded and eluted first with methanol/dichloromethane (1:1) and then eluted with 2 M ammonia in methanol) to give the title compound (8.7 mg, 0.023 mmol, 48% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 6.44 (d, J = 1.3 Hz, 1H), 4.00 (dd, J = 10.5, 8.5 Hz, 2H), 3.93 (s, 2H), 3.67 (dd, J = 10.4, 7.0 Hz, 2H), 3.42 (s, 2H), 3.07 (p, J = 7.7 Hz, 1H), 2.71 (dd, J = 14.9, 6.6 Hz, 4H), 2.61 (t, J = 5.7 Hz, 2H); MS (APCI ⁺ ) m/z 371.4 [M+H] ⁺ .

Example 67: 5-{2-[(azetidin-3-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 166)

Example 67A: 6 '-(benzyloxy)-8' - fluoro-3 ',4' -dihydro-1 'H-spiro[[1,3]dioxolane-2,2' -naphthalene]

[00410] To a solution of the product from Example 22B (100 g, 348 mmol) and benzyl alcohol (50.5 mL, 488 mmol) in dioxane (200 mL) were added sodium tert -butoxide (40.2 g, 418 mmol), N,N' -diphenethyloxalamide (1.032 g, 3.48 mmol), and copper(I) iodide (0.663 g, 3.48 mmol). The resulting mixture was degassed (3 x vacuum/nitrogen purge) and then heated to 80 °C. After 48 h, water (1 L) was added and the resulting mixture was cooled to ambient temperature. The mixture was filtered and the solid was washed with water (200 mL). The filtrate was extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (1 L) and filtered through ^Celite® (100 g). The filtrate was concentrated in vacuo. The resulting solid was triturated with isopropanol (200 mL) to give 85 g (244 mmol, 78% yield) of the title compound. ¹ H NMR (400 MHz, _CDCl3 ) δ ppm. 7.46-7.28 (m, 5H), 6.74-6.60 (m, 2H), 5.07 (s, 2H), 4.00-3.88 (m, 4H), 2.86 (t, J =6.7 Hz, 2H), 2.72 (s, 2H), 1.83 (t, J =6.7 Hz, 2H); MS (CIAD ⁺ ) m/z 315 [M+H] ⁺ .

Example 67B: 6 '-(benzyloxy)-7' - bromo-8' - fluoro-3 ',4' - dihydro-1 'H-spiro[[1,3]dioxolane-2,2' -naphthalene]

[00411] To a solution of 2,2,6,6-tetramethylpiperidine (164 mL, 964 mmol) in tetrahydrofuran (500 mL) at 0 °C was added a solution of n -butyl lithium (360 mL, 2.5 M in hexane, 900 mL) slowly over 40 minutes. After stirring for 30 minutes, the reaction mixture was diluted with tetrahydrofuran (500 mL) and cooled to -78 °C. A solution of the product of Example 67A (202.11 g, 643 mmol) in tetrahydrofuran (500 mL) was added slowly over 30 minutes such that the internal temperature remained below -70 °C. After 2 h, 1,2-dibromo-1,1,2,2-tetrafluoroethane (92 mL, 772 mmol) was added slowly to maintain the internal temperature below -60 °C. After complete addition, the reaction mixture was warmed to -10 °C, then quenched with saturated aqueous ammonium chloride (500 mL) and diluted with water (1.5 L) and ethyl acetate (2 L). The layers were separated, and the organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and brine (500 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was diluted with isopropanol (500 mL), then warmed to 50 °C and slowly cooled to ambient temperature. The resulting solid was collected by filtration to give the title compound (130.3 g, 331 mmol, 51.5% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.50-7.28 (m, 5H), 6.53 (d, J =1.6 Hz, 1H), 5.12 (s, 2H), 4.10-3.97 (m, 4H), 2.93 (t, J =6.7 Hz, 2H), 2.89 (s, 2H), 1.92 (t, J =6.7 Hz, 2H); MS (CIAD ⁺ ) m/z 393 [M+H] ⁺ .

Example 67C: tert-butyl {[6 '-(benzyloxy)-8' - fluoro-3 ',4' - dihydro-1'H -spiro[[1,3]dioxolane-2,2' -naphthalene]-7 ' -yl]amino}acetate

[00412] To a suspension of the product from Example 67B (14.17 g, 36 mmol), cesium carbonate (35.2 g, 108 mmol), BrettPhos (0.387 g, 0.721 mmol), and BrettPhos Pd G3 precatalyst (0.653 g, 0.721 mmol) in 1,4-dioxane (280 mL) was added tert -butyl glycinate (7.39 mL, 54.1 mmol). The resulting suspension was degassed (5×vacuum/nitrogen purge) and then heated to 90 °C. After 16 h, the reaction mixture was cooled to below 30 °C and additional BrettPhos Pd G3 precatalyst (0.653 g, 0.721 mmol) was added. The reaction mixture was degassed (5× vacuum/nitrogen purge) and then heating was resumed to 90 °C. After 7 h, the reaction mixture was cooled to below 30 °C and additional BrettPhos Pd G3 precatalyst (0.653 g, 0.721 mmol) was added. The reaction mixture was degassed (5× vacuum/nitrogen purge) and then heated to 90 °C. After 16 h, the reaction mixture was cooled to below 30 °C and additional BrettPhos Pd G3 precatalyst (0.328 g, 0.362 mmol) was added. The reaction mixture was degassed (5× vacuum/nitrogen purge) and then heated to 90 °C. After 4 h, the reaction mixture was cooled to ambient temperature, quenched with saturated aqueous ammonium chloride (70 mL), and diluted with water (70 mL) and ethyl acetate (140 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 70 mL). The organic layers were combined, washed with brine (42 mL), dried over anhydrous sodium sulfate, and filtered. Silica (35 g) was added to the filtrate, and the mixture was concentrated in vacuo to a powder, which was dry loaded onto a Teledyne ISCO 220 g Gold silica gel column and purified by running a gradient of 0-40% ethyl acetate in heptanes supplemented with 0.1% triethylamine to give 12.44 g (28.1 mmol, 78% yield) of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.50-7.27 (m, 5H), 6.45 (d, J =1.4 Hz, 1H), 5.06 (s, 2H), 4.42 (s, 1H), 4.10-3.97 (m, 5H), 3.97-3.91 (m, 2H), 2.88 (t, J =6.8 Hz, 2H), 2.84 (s, 2H), 1.90 (t, J =6.6 Hz, 2H), 1.44 (s, 9H); MS (CIAD ⁺ ) m/z 444 [M+H] ⁺ .

Example 67D: tert-butyl {[6 '-(benzyloxy)-8' - fluoro-3 ',4' -dihydro-1 'H-spiro[[1,3]dioxolane-2,2' -naphthalene]-7 ' -yl]({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino}acetate

[00413] To a solution of chlorosulfonyl isocyanate (3.65 mL, 42.1 mmol) in dichloromethane (124 mL) was added allyl alcohol (2.86 mL, 42.1 mmol) dropwise. After 30 min, a previously prepared solution of the product of Example 67C (12.44 g, 28.1 mmol) and N,N -diisopropylethylamine (9.8 mL, 56.1 mmol) in dichloromethane (62 mL) was slowly added via an addition funnel. After 45 min, the reaction mixture was quenched with water (125 mL) and stirred for 5 min. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 62 mL). The organic layers were combined, washed with 1 M aqueous sodium bisulfate (62 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound, which was used without purification in the next step. MS (APCI ⁺ ) m/z 624 [M+NH ₄ ] ⁺ .

Example 67E: 5-[6 '-(benzyloxy)-8' - fluoro-3 ',4' -dihydro-1 'H-spiro[[1,3]dioxolane-2,2' - naphthalene]-7 ' - yl]-1 λ ^6,2,5 -thiadiazolidine-1,1,3-trione

[00414] To a solution of the crude product of Example 67D (17.0 g, 28.1 mmol) in methanol (340 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.648 g, 0.561 mmol), followed by a solution of sodium methoxide (38.5 mL, 25 wt % in methanol, 168 mmol). The resulting mixture was degassed (3×vacuum/nitrogen purge) and then heated to 60 °C. After 1 h, the reaction mixture was cooled to ambient temperature, quenched with 1 M hydrochloric acid (190 mL), diluted with ethyl acetate (85 mL), and partially concentrated in vacuo to remove methanol. The resulting biphasic mixture was extracted with ethyl acetate (3×85 mL). The organic layers were combined, washed with brine (51 mL), dried over anhydrous sodium sulfate, filtered through ^Celite® (5 g), and concentrated in vacuo. The residue was suspended in tert -butyl methyl ether (85 mL), heated to reflux, and then cooled to ambient temperature. The resulting solid was collected by filtration, washed with cold filtrate and then cold tert -butyl methyl ether (34 mL), and dried in a vacuum oven at 50 °C to give 7.95 g (17.72 mmol, 63.2% yield) of the title compound. MS (APCI ⁺ ) m/z 449 [M+H] ⁺ .

Example 67F: 5-[3-(benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00415] The product from Example 67E (1.5 g, 3.34 mmol) was suspended in 88% formic acid (7.5 mL, 196 mmol). After 45 min, the reaction mixture was diluted by dropwise addition of brine (15 mL). The resulting solid was collected by filtration, washed with water (4 x 7.5 mL), and dried in a vacuum oven at 50 °C to give 1.33 g (3.30 mmol, 99% yield) of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.47 (d, J = 6.8 Hz, 2H), 7.45-7.28 (m, 3H), 7.05 (s, 1H), 5.19 (s, 2H), 4.40 (s, 2H), 3.47 (s, 2H), 3.06 (t, J = 6.7 Hz, 2H), 2.50 (t, J = 6.7 Hz, 2 H); MS (APCI ⁺ ) m/z 422 [M+NH ₄ ] ⁺ .

Example 67G: 5-{3-(benzyloxy)-7-[(4,4-difluorobutyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00416] To a solution of the product of Example 67F (0.5 g, 1.24 mmol) in ethanol (10 mL) was added 4,4-difluorobutan-1-amine hydrochloride (0.270 g, 1.86 mmol) followed by triethylamine (0.517 mL, 3.71 mmol). After 30 min, sodium cyanoborohydride (0.093 g, 1.48 mmol) was added as a solid. The mixture was allowed to stir for 16 h and then quenched with ammonium hydroxide (0.14 mL, 7.42 mmol) and diluted with acetonitrile (10 mL) and water (2 mL). ^Celite® (5 g) was added and the mixture was concentrated in vacuo to give a powder. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reversed phase C18 column, eluting with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.386 g, 0.776 mmol, 63% yield. MS ( ^APCI ) m/z 498 [M+H] ⁺ .

Example 67H: 5-{2-[(azetidin-3-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00417] To a suspension of the product of Example 67G (0.386 g, 0.776 mmol) and pentamethylbenzene (0.230 g, 1.55 mmol) in dichloromethane (7.7 mL) at -78 °C was added a solution of boron trichloride (4.66 mL, 1 M in dichloromethane, 4.66 mmol) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (4 mL) and then ethanol (4 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The residue was triturated with heptanes (3 x 8 mL), 1:1 ethyl acetate/heptanes (2 x 4 mL), dichloromethane (2 x 4 mL), and acetonitrile (3 x 4 mL) and then dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (0.297 g, 0.669 mmol, 86% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.17 (br s, 1H), 9.00 (br s, 2H), 6.54 (s, 1H), 6.15 (tt, J = 56.6, 4.2 Hz, 1H), 4.32 (s, 2H), 3.48-3.40 (m, 1H), 316-3.02 (m, 3H), 2.88-2.70 (m, 2H), 2.61 (dd, J = 16.1, 10.0 Hz, 1H), 2.24-2.16 (m, 1H), 2.09-1.86 (m, 2H), 1.84-1.67 (m, 3H); MS (APCI ⁺ ) m/z 408 [M+H] ⁺ .

Example 68: 5-(1-fluoro-3-hydroxy-7-{(3-methylbutyl)[2-(pyridin-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 167)

[00418] To a solution of the product from Example 22I (0.3 g, 0.596 mmol) and 2-(2-aminoethyl)pyridine (0.107 mL, 0.894 mmol) in acetonitrile (6 mL) at room temperature was added sodium cyanoborohydride (0.075 g, 1.191 mmol). After 18 h, isovaleraldehyde (0.257 mL, 2.383 mmol) was added. After 23 h, a solution of hydrogen chloride (1.489 mL, 5.96 mmol, 4 M in dioxane) was added dropwise (vigorous gas evolution). After 4 h, the reaction mixture was quenched with ammonium hydroxide (0.090 mL, 4.77 mmol) and then diluted with acetonitrile (4 mL) and water (2 mL). Celite® (2 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0363 g, 0.074 mmol, 12.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.17 (s, 1H), 8.51 (dd, J =4.8, 1.7 Hz, 1H), 7.75 (tt, J =7.2, 3.6 Hz, 1H), 7.62 (s, 2H), 7.37 (d, J =7.8 Hz, 1H), 7.27 (dd, J =7.5, 4.8 Hz, 1H), 6.44 (s, 1H), 3.90 (s, 2H), 3.81-3.65 (m, 1H), 3.62-3.50 (m, 2H), 3.25-3.16 (m, 2H), 3.07-2.97 (m, 1H), 2.84-2.73 (m, 2H), 2.20-2.10 (m, 1H), 1.86-1.75 (m, 1H), 163-1.51 (m, 3H), 1.48-1.33 (m, 1H), 0.86 (d, J = 5.7 Hz, 6H); MS (CIAD ⁺ ) m/z 491 [M+H] ⁺ .

Example 69: 5-{8-fluoro-6-hydroxy-2-[(spiro[2.3]hexan-5-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 168)

Example 69A: 5-{6-(benzyloxy)-8-fluoro-2-[(spiro[2.3]hexan-5-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00419] A suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate, the product of Example 54A (nominally 0.25 mmol, 1 equivalent), potassium carbonate (175 mg, 1.27 mmol, 5.0 equivalents), and 5-(bromomethyl)spiro[2,3]hexane (89 mg, 0.51 mmol, 2.0 equivalents) in acetonitrile (1.7 mL) was sealed in a 4 mL vial. The sealed vial was placed on a heating block preheated to 60 °C. The reaction mixture was stirred at 60 °C for 18 h and then cooled to 23 °C. The cooled mixture was filtered through a pad of diatomaceous earth (1.0 cm × 0.5 cm). The filter cake was washed with acetonitrile (5 × 1.0 mL). The filtrates were combined and the combined filtrates were concentrated. The resulting residue was used without further purification in the next step. MS (APCI ⁺ ) m / z 486 [M+H] ⁺ .

Example 69B: 5-{8-fluoro-6-hydroxy-2-[(spiro[2.3]hexan-5-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00420] A solution of boron trichloride in dichloromethane (1.0 M, 1.5 mL, 1.5 mmol, 6.0 equivalents) was slowly added through the side of the flask to a suspension of the product from Example 69A (nominally 0.25 mmol, 1 equivalent) and pentamethylbenzene (113 mg, 0.76 mmol, 3.0 equivalents) in dichloromethane (1.3 mL) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C and then slowly diluted with ethanol (0.8 mL) at -78 °C. The diluted mixture was warmed to 23 °C over 30 min and concentrated. The resulting residue was triturated with heptanes (3 x 5 mL). The resulting residue was purified by reverse-phase flash column chromatography (100 g RediSep Rf Gold ^® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min) to give the title compound (12 mg, 0.030 mmol, 12% yield, three steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.68 (br, 1H), 6.56 (s, 1H), 3.94 (s, 2H), 3.16-2.83 (m, 4H), 2.22-2.01 (m, 4H), 0.33-0.33 (m, 4H). MS (APCI ⁺ ) m / z 396 [M+H] ⁺ .

Example 70: 5-(1-fluoro-3-hydroxy-7-{[2-(trifluoromethoxy)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 169)

[00421] The title compound was prepared using the procedures described in Example 26 substituting 2,2-difluoro-2-phenylethanamine, hydrochloric acid for 2-(trifluoromethoxy)ethanamine, hydrochloric acid. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.20 (br s, 1H), 8.92 (br s, 4H), 6.47 (s, 1H), 4.35 (m, 2H), 3.93 (s, 2H), 3.41 (m, 2H), 3.07 (m, 1H), 2.75 (m, 2H), 2.55 (m, 2H), 2.15 (m, 1H), 1.69 (m, 1H); MS (IER ^- ) m/z 426 [MH] ^- .

Example 71: 5-[8-fluoro-6-hydroxy-2-(3-hydroxy-3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 170)

Example 71A: 5-[6-(benzyloxy)-8-fluoro-2-(3-hydroxy-3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00422] A mixture of the product of Example 65A (139 mg, 0.275 mmol), 4-bromo-2-methylbutan-2-ol (59.7 mg, 0.358 mmol), and cesium carbonate (448 mg, 1.375 mmol) in N,N -dimethylformamide (1.5 mL) was stirred at 70 °C for 2.5 h and then at room temperature for 3 days. The mixture was quenched with methanol/water (2:1, 5 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm, 50×100 mm column, flow rate 140 mL/min, 5-65% gradient of methanol in water (0.1% trifluoroacetic acid)] to afford the title compound (53 mg, 0.090 mmol, yield 33%). MS (ESI ^- ) m/z 476 [MH] ^- .

Example 71B: 5-[8-fluoro-6-hydroxy-2-(3-hydroxy-3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00423] To a mixture of 1,2,3,4,5-pentamethylbenzene (50.1 mg, 0.338 mmol) and Example 71A (50 mg, 0.085 mmol) in dichloromethane (3 mL) at -78 °C was added trichloroborane (0.93 mL, 0.930 mmol, 1 M in dichloromethane). The mixture was stirred at -78 °C for 10 min, then at -20 °C for 30 min. The mixture was quenched with ethanol (3 mL) and concentrated under reduced pressure. The residue was washed with heptane (4 x 4 mL), dichloromethane (6 x 3 mL), and dried under reduced pressure to give the title compound (39 mg, 0.078 mmol, 92% yield). ¹ H NMR (500 MHz, DMSO _-d6 ) δ ppm 10.48 (lat s, 1H), 10.34 (lat s, 1H), 6.66 (s, 1H), 4.45 (m, 1H), 4.32 (s, 2H), 4.12 (m, 1H), 3.69 (m, 2H), 3.29 (m, 3H), 3.14 (m, 1H), 2.99 (m, 1H), 1.88 (t, J =7 Hz, 2H), 1.16 (s, 6H); MS (ESI ⁺ ) m/z 388 [M+H] ⁺ .

Example 72: 3-hydroxybutyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate (Compound 171)

Example 72A: 3-hydroxybutyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00424] To a solution of the product of Example 44H (116 mg, 0.236 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (538 mg, 4.72 mmol). The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give the intermediate, 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylic acid. To this intermediate was added 4-bromobutan-2-ol (45.1 mg, 0.295 mmol) and cesium carbonate (384 mg, 1.180 mmol) in N,N -dimethylformamide (1 mL). The mixture was stirred at 50°C for 18 h and cooled to room temperature. The mixture was diluted with ethyl acetate (80 mL), washed with 0.2 N aqueous HCl (15 mL) and brine (2×15 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in methanol/ N,N -dimethylformamide (2:1, 3 mL) and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm, 25×150 mm column, flow rate 80 mL/min, 0-70% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (25 mg, 0.048 mmol, yield 20.2%) as the ammonium salt. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 7.53 (b, s, 4H), 6.48 (s, 1H), 4.52 (m, 1H), 4.37 (s, 2H), 4.07 (m, 2H), 3.92 (s, 2H), 3.68 (m, 1H), 3.52 (m, 2H), 2.67 (m, 2H), 1.60 (m, 2H), 1.04 (d, J =7 Hz, 3H); MS (IER ^- ) m/z 506 [MH] ^- .

Example 72B: 3-hydroxybutyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00425] To a mixture of 1,2,3,4,5-pentamethylbenzene (16.65 mg, 0.112 mmol) and the product of Example 72A (19 mg, 0.037 mmol) in dichloromethane (2 mL) at -78 °C was added trichloroborane (0.441 mL, 0.441 mmol, 1 M in dichloromethane). The mixture was stirred at -78 °C for 10 min, then at -20 °C for 20 min. The mixture was quenched with ethanol (3 mL) and concentrated under reduced pressure. The residue was washed with heptane (4 x 4 mL) and dichloromethane (6 x 3 mL). The resulting residue was dissolved in methanol/ N,N -dimethylformamide (2:1, 3 mL) and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm, 25×150 mm column, flow rate 80 mL/min, 0-50% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (10 mg, 0.023 mmol, yield 61.5%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.53 (b, s, 4H), 6.48 (s, 1H), 4.52 (m, 1H), 4.37 (s, 2H), 4.07 (m, 2H), 3.92 (s, 2H), 3.68 (m, 1H), 3.52 (m, 2H), 2.67 (m, 2H), 1.60 (m, 2H), 1.04 (d, J =7 Hz, 3H); MS (IER ^- ) m/z 416 [MH] ^- .

Example 73: 5-{1-fluoro-3-hydroxy-7-[3-(propan-2-yl)pyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 172)

[00426] To a solution of the product of Example 67F (0.1 g, 0.247 mmol) in ethanol (2 mL) was added 3-(propan-2-yl)pyrrolidine hydrochloride (0.056 g, 0.371 mmol) followed by triethylamine (0.103 mL, 0.742 mmol). After 30 min, sodium cyanoborohydride (0.019 g, 0.297 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.028 mL, 1.48 mmol) then diluted with acetonitrile (2 mL) and water (1 mL). ^Celite® (1 g) was added and the mixture was concentrated in vacuo to give a powder. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-1-fluoro-7-[3-(propan-2-yl)pyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.08 g, 0.159 mmol, 64.4% yield). MS ( ^APCI ) m/z 502 [M+H] ⁺ .

[00427] To a suspension of 5-{3-(benzyloxy)-1-fluoro-7-[3-(propan-2-yl)pyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.08 g, 0.159 mmol) and pentamethylbenzene (0.047 g, 0.319 mmol) in dichloromethane (2.9 mL) at -78°C was added a solution of boron trichloride (0.96 mL, 1 M in dichloromethane, 0.96 mmol) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The residue was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), dichloromethane (2 x 2 mL), and acetonitrile (2 x 1 mL) and then dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (0.0493 g, 0.110 mmol, 69.1% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 10.85 (s, 1H), 10.15 (s, 1H), 6.54 (s, 1H), 4.32 (d, J =1.6 Hz, 2H), 3.73-3.52 (m, 1H), 3.52-3.42 (m, 2H), 3.37-3.04 (m, 3H), 2.92-2.82 (m, 1H), 2.81-2.66 (m, 3H), 2.37-2.20 (m, 1H), 2.16-1.91 (m, 2H), 1.85-1.62 (m, 1H), 1.62-1.48 (m, 1H), 0.95-0.87 (m, 6H); MS (CIAD ⁺ ) m/z 412 [M+H] ⁺ .

Example 74: 5-{7-[(2-cyclohexylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 173)

[00428] To a solution of the product of Example 67F (0.1 g, 0.247 mmol) in ethanol (2 mL) was added 2-cyclohexylethanamine (0.047 g, 0.371 mmol). After 30 min, sodium cyanoborohydride (0.019 g, 0.297 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.028 mL, 1.484 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-7-[(2-cyclohexylethyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0517 g, 0.100 mmol, 40.5% yield). MS ( ^APCI ) m/z 516 [M+H] ⁺ .

[00429] To a suspension of 5-{3-(benzyloxy)-7-[(2-cyclohexylethyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0517 g, 0.100 mmol) and pentamethylbenzene (0.030 g, 0.201 mmol) in dichloromethane (2 mL) at -78 °C was added a solution of boron trichloride (0.602 mL, 1 M in dichloromethane, 0.602 mmol) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) and then ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), dichloromethane (2 x 2 mL), and acetonitrile (2 x 1 mL) and then dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (0.0452 g, 0.098 mmol, 98% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.17 (s, 1H), 8.97 (tk, J =12.0, 6.1 Hz, 2H), 6.54 (s, 1H), 4.31 (s, 2H), 3.44-3.35 (m, 1H), 3.13 (dd, J =15.9, 5.5 Hz, 1H), 3.01 (dk, J =12.4, 6.4 Hz, 2H), 2.82 (dt, J =17.1, 4.5 Hz, 1H), 2.73 (ddd, J =17.3, 11.4, 5.4 Hz, 1H), 2.61 (dd, J =16.0, 10.1 Hz, 1H), 2.25-2.18 (m, 1H), 1.80-1.58 (m, 6H), 1.61-1.51 (m, 2H), 1.35 (td, J = 8.7, 7.0, 3.7 Hz, 1H), 1.18 (dddd, J = 24.2, 15.2, 12.2, 6.2 Hz, 3H), 0.92 (q, J = 11.8 Hz, 2H); MS (APCI ⁺ ) m/z 426 [M+H] ⁺ .

Example 75: 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 174)

[00430] To a solution of the product of Example 67F (0.1 g, 0.247 mmol) in ethanol (2 mL) was added 3,3-dimethylbutylamine (0.038 g, 0.371 mmol). After 30 min, sodium cyanoborohydride (0.019 g, 0.297 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.028 mL, 1.48 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). ^Celite® (1 g) was added and the mixture was concentrated in vacuo to give a white powder. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-7-[(3,3-dimethylbutyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0714 g, 0.146 mmol, 59% yield). MS (APCI ⁾ m/z 490 [M+H] ⁺ .

[00431] To a suspension of 5-{3-(benzyloxy)-7-[(3,3-dimethylbutyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0714 g, 0.146 mmol) and pentamethylbenzene (0.043 g, 0.292 mmol) in dichloromethane (2.14 mL) at -78°C was added a solution of boron trichloride (0.875 mL, 1 M in dichloromethane, 0.875 mmol) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), dichloromethane (2 x 2 mL), and acetonitrile (2 x 1 mL), then dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (0.0573 g, 0.131 mmol, 90% yield). ¹ H NMR (600 MHz, DMSO -d ₆ ) δ ppm. 10.08 (s, 1H), 8.91 (dt, J =29.1, 5.8 Hz, 2H), 6.53 (s, 1H), 4.29 (s, 2H), 3.42 (s, 1H), 3.14 (dd, J =15.9, 5.5 Hz, 1H), 3.00 (dk, J =12.3, 6.4 Hz, 2H), 2.83 (dt, J =17.3, 4.5 Hz, 1H), 2.74 (ddd, J =17.3, 11.6, 5.5 Hz, 1H), 2.61 (dd, J =15.9, 10.4 Hz, 1H), 2.25-2.20 (m, 1H), 1.73 (cd, J =11.8, 5.3 Hz, 1H), 1.60-1.54 (m, 2H), 0.93 (s, 9H); MS (CIAD ⁺ ) m/z 400 [M+H] ⁺ .

Example 76: 5-[7-(butylamino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 175)

[00432] To a solution of the product of Example 67F (0.1 g, 0.247 mmol) in ethanol (2 mL) was added butylamine (0.037 mL, 0.371 mmol). After 30 min, sodium cyanoborohydride (0.019 g, 0.297 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.028 mL, 1.484 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). ^Celite® (1 g) was added and the mixture was concentrated in vacuo to give a powder. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-[3-(benzyloxy)-7-(butylamino)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0803 g, 0.174 mmol, 70.4% yield). MS ( ^APCI ) m/z 462 [M+H] ⁺ .

[00433] To a suspension of 5-[3-(benzyloxy)-7-(butylamino)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0803 g, 0.174 mmol) and pentamethylbenzene (0.052 g, 0.348 mmol) in dichloromethane (1.6 mL) at -78 °C was slowly added a solution of boron trichloride (1.04 mL, 1.04 mmol, 1 M in dichloromethane) along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) and then ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), dichloromethane (2 x 2 mL), and acetonitrile (2 x 1 mL) and then dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (0.0665 g, 0.163 mmol, 94% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 10.12 (s, 1H), 8.90 (ddd, J =22.0, 12.4, 6.5 Hz, 2H), 6.53 (s, 1H), 4.30 (s, 2H), 3.46-3.35 (m, 1H), 3.12 (dd, J =16.0, 5.6 Hz, 1H), 3.00 (dk, J =12.5, 6.6 Hz, 2H), 2.82 (dt, J =17.2, 4.5 Hz, 1H), 2.74 (ddd, J =17.2, 11.4, 5.5 Hz, 1H), 2.60 (dd, J =16.1, 10.2 Hz, 1H), 2.24-2.17 (m, 1H), 1.73 (cd, J =11.8, 4.7 Hz, 1H), 1.63 (dk, J =12.7, 8.1, 7.5 Hz, 2H), 1.37 (g, J =7.4 Hz, 2H), 0.91 (t, J =7.3 Hz, 3H); MS (CIAD ⁺ ) m/z 372 [M+H] ⁺ .

Example 77: 5-{(7 S )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 176)

[00434] The product of Example 24 (0.299 g, 0.660 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a CO ₂ pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical CO ₂ supplied by a 350 psi dewar of bone dry non-certified CO ₂ with methanol modifier (0.1% triethylamine) at a flow rate of 80 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol to a concentration of 15 mg/mL. The sample was loaded into the modifier stream in 0.25 mL (3.75 mg) injections. The mobile phase was maintained isocratically at 40% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm × 250 mm id CHIRALPAK® IC column with 5 μm particles. The enantiomer peak eluting early gave the title compound (0.1069 mg, 0.236 mmol, 17.4% yield). ¹ H NMR and MS data were identical to those of Example 24. The absolute stereochemistry was assigned by analogy with the chromatographic elution order of the product of Example 18.

Example 78: 5-{(7 R )-1-fluoro-3-hydroxy-7-[(4,4,4-trifluoro-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 177)

[00435] The product of Example 24 (0.2993 g, 0.660 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a CO ₂ pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical CO ₂ supplied by a 350 psi dewar of bone dry non-certified CO ₂ with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol to a concentration of 15 mg/mL. The sample was loaded into the modifier stream in 0.25 mL (3.75 mg) injections. The mobile phase was maintained isocratically at 40% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm × 250 mm id CHIRALPAK® IC column with 5 μm particles. The late eluting enantiomer peak gave the title compound (0.0723 mg, 0.159 mmol, 48.3% yield). ¹ H NMR and MS data were identical to those of Example 24. The absolute stereochemistry was assigned by analogy with the chromatographic elution order of the product of Example 19.

Example 79: 5-{7-[(2-cyclopentylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 178)

[00436] To a solution of the product of Example 67F (0.05 g, 0.124 mmol) in ethanol (1 mL) was added 2-cyclopentylethanamine (0.021 g, 0.185 mmol). After 30 min, sodium cyanoborohydride (0.009 g, 0.148 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.014 mL, 0.742 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-7-[(2-cyclopentylethyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0338 g, 0.067 mmol, 54.5% yield) as an off-white (beige) solid. MS (APCI ⁾ m/z 502 [M+H] ⁺ .

[00437] To a suspension of 5-{3-(benzyloxy)-7-[(2-cyclopentylethyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0338 g, 0.067 mmol) and pentamethylbenzene (0.020 g, 0.135 mmol) in dichloromethane (1.4 mL) at -78°C was added a solution of boron trichloride (0.404 mL, 0.404 mmol, 1 M in dichloromethane) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), dichloromethane (2 x 2 mL), and acetonitrile (2 x 1 mL), then dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (0.0264 g, 0.059 mmol, 87% yield). ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm. 10.16 (s, 1H), 9.00-8.82 (m, 2H), 6.53 (s, 1H), 4.32 (s, 2H), 3.41 (s, 1H), 3.12 (dd, J =16.0, 5.5 Hz, 1H), 3.00 (dk, J =12.0, 6.3 Hz, 2H), 2.83 (dt, J =16.9, 4.4 Hz, 1H), 2.74 (ddd, J =17.1, 11.4, 5.4 Hz, 1H), 2.60 (dd, J =16.1, 10.2 Hz, 1H), 2.24-2.18 (m, 1H), 1.89-1.44 (m, 9H), 1.20-1.05 (m, 2H); MS (CIAD ⁺ ) m/z 412 [M+H] ⁺ .

Example 80: 5-[2-(2-cyclohexylethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 179)

Example 80A: 5-[6-(benzyloxy)-2-(2-cyclohexylethyl)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00438] A suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate, the product of Example 54A (nominally 0.25 mmol, 1 equivalent), potassium carbonate (176 mg, 1.27 mmol, 5.0 equivalent), and (2-bromoethyl)cyclohexane (99 mg, 0.51 mmol, 2.0 equivalent) in acetonitrile (0.8 mL) was sealed in a 4 mL vial. The sealed vessel was placed on a heating block preheated to 60 °C. The reaction mixture was stirred at 60 °C for 18 h and then cooled to 23 °C. The cooled product mixture was filtered through a pad of diatomaceous earth (1.0 cm × 0.5 cm). The filter cake was washed with acetonitrile (5 × 1.0 mL). The filtrates were combined and the combined filtrates were concentrated. The resulting residue was used without further purification in the next step. MS (APCI ⁺ ) m / z 502 [M+H] ⁺ .

Example 80B: 5-[2-(2-cyclohexylethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00439] A solution of boron trichloride in dichloromethane (1.0 M, 2.5 mL, 2.5 mmol, 10.0 equivalents) was slowly added down the side of the flask to a suspension of the product of Example 80A (nominally 0.25 mmol, 1 equivalent) and pentamethylbenzene (113 mg, 0.76 mmol, 3.0 equivalents) in dichloromethane (1.3 mL) at -78 °C. The reaction mixture was stirred for 15 min at -78 °C. The reaction mixture was then placed in an ice bath at 0 °C and stirred for 1.5 h at 0 °C. The mixture was then slowly diluted with ethanol (0.8 mL) at -78 °C. The diluted mixture was warmed to 23 °C over 30 min and concentrated. The resulting residue was triturated with heptanes (3×5 mL). The resulting residue was purified by reverse-phase flash column chromatography (100 g RediSep Rf ^Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min) to give the title compound (32 mg, 0.078 mmol, 31% yield, three steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.69 (br, 1H), 6.58 (s, 1H), 4.57-3.94 (m, 2H), 3.78 (s, 2H), 3.28-3.14 (m, 4H), 3.00 (s, 2H), 1.75-1.57 (m, 7H), 1.38-1.07 (m, 4H), 1.00-0.89 (m, 2H); MS (APCI ⁺ ) m / z 412 [M+H] ⁺ .

Example 81: 5-{1-fluoro-3-hydroxy-7-[(2-hydroxyethyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 180)

[00440] To a solution of the product of Example 67F (0.05 g, 0.124 mmol) in ethanol (1 mL) was added 2-aminoethyl isopropyl ether (0.019 g, 0.185 mmol). After 30 min, sodium cyanoborohydride (0.009 g, 0.148 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.014 mL, 0.742 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-[3-(benzyloxy)-1-fluoro-7-({2-[(propan-2-yl)oxy]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0390 g, 0.079 mmol, 64.2% yield). MS ( ^APCI ) m/z 492 [M+H] ⁺ .

[00441] To a suspension of 5-[3-(benzyloxy)-1-fluoro-7-({2-[(propan-2-yl)oxy]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0390 g, 0.079 mmol) and pentamethylbenzene (0.024 g, 0.159 mmol) in dichloromethane (1.6 mL) at -78°C was added a solution of boron trichloride (0.476 mL, 1 M in dichloromethane, 0.476 mmol) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), dichloromethane (2 x 2 mL), and acetonitrile (2 x 1 mL) and then dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (0.0262 g, 0.073 mmol, 92% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 10.22 (s, 1H), 9.07-8.97 (m, 2H), 6.55 (s, 1H), 4.34 (s, 2H), 3.72 (t, J =5.2 Hz, 2H), 3.44 (s, 1H), 3.19-3.06 (m, 5H), 2.89-2.78 (m, 1H), 2.80-2.67 (m, 1H), 2.62 (dd, J =16.0, 10.4 Hz, 1H), 2.28-2.20 (m, 1H), 1.74 (cd, J =11.8, 5.4 Hz, 1H); MS (CIAD ⁺ ) m/z 360 [M+H] ⁺ .

Example 82: 5-{1-fluoro-3-hydroxy-7-[2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 181)

[00442] To a solution of the product of Example 67F (0.05 g, 0.124 mmol) in ethanol (1 mL) was added 2-isopropylmorpholine (0.024 g, 0.185 mmol). After 30 min, sodium cyanoborohydride (0.009 g, 0.148 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.014 mL, 0.742 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-1-fluoro-7-[2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0321 g, 0.062 mmol, 50.2% yield). MS ( ^APCI ) m/z 518 [M+H] ⁺ .

[00443] A suspension of 5-{3-(benzyloxy)-1-fluoro-7-[2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0321 g, 0.062 mmol) and 10% palladium hydroxide on carbon (0.064 g, 0.228 mmol, 50 wt % in water) in tetrahydrofuran (3 mL) was stirred for 22 h under 100 psi of hydrogen pressure. After filtration, ^Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0025 g, 0.00585 mmol, 9.4% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 9.05 (lat s, 1H), 7.15 (lat s, 1H), 6.44 (s, 1H), 3.93 (s, 2H), 3.89 (d, J =9.4 Hz, 1H), 3.61-3.45 (m, 2H), 2.89-2.74 (m, 4H), 2.75-2.63 (m, 2H), 2.58-2.46 (m, 1H), 2.12-2.00 (m, 1H), 1.67 (k, J =6.9 Hz, 1H), 1.58 (s, 1H), 0.90 (d, J =6.8 Hz, 3H), 0.88 (d, J =6.7 Hz, 3H); MS (CIAD ⁺ ) m/z 428 [M+H] ⁺ .

Example 83: 5-{1-fluoro-3-hydroxy-7-[(2 R )-2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 182)

[00444] To a solution of the product of Example 67F (0.05 g, 0.124 mmol) in ethanol (1 mL) was added (R)-2-isopropylmorpholine (0.024 g, 0.185 mmol). After 30 min, sodium cyanoborohydride (0.009 g, 0.148 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.014 mL, 0.742 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-1-fluoro-7-[(2 R )-2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.027 g, 0.052 mmol, 42.3% yield). MS ( ^APCI ) m/z 518 [M+H] ⁺ .

[00445] A suspension of 5-{3-(benzyloxy)-1-fluoro-7-[(2 R )-2-(propan-2-yl)morpholin-4-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0271 g, 0.052 mmol) and 10% palladium hydroxide on carbon (0.055 g, 0.196 mmol, 50 wt % in water) in a mixture of water (0.5 mL) and tetrahydrofuran (4 mL) was stirred for 20.5 h under 113 psi of hydrogen pressure. After filtration, ^Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 50 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.011 g, 0.026 mmol, 49.1% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.05 (lat s, 1H), 7.15 (lat s, 1H), 6.44 (s, 1H), 3.93 (s, 2H), 3.89 (d, J =9.4 Hz, 1H), 3.61-3.45 (m, 2H), 2.89-2.74 (m, 4H), 2.75-2.63 (m, 2H), 2.58-2.46 (m, 1H), 2.12-2.00 (m, 1H), 1.67 (k, J =6.9 Hz, 1H), 1.58 (s, 1H), 0.90 (d, J =6.8 Hz, 3H), 0.88 (d, J =6.7 Hz, 3H); MS (CIAD ⁺ ) m/z 428 [M+H] ⁺ .

Example 84: 5-{8-fluoro-6-hydroxy-2-[(pyrrolidin-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 183)

Example 84A: 5-(8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[00446] The product of Example 44H (200 mg, 0.41 mmol) and tetrahydrofuran (5 mL) were added to 10% wet Pd(OH) ₂ /C (114 mg, 0.41 mmol) in a 20 mL Barnstead Hast C reactor and the mixture was stirred at 25 °C for 19 h under 65 psi of hydrogen pressure. Additional Pd/C (5%, wet JM#9) (400 mg, 1.75 mmol) was added and the reaction mixture was stirred at 30 °C for an additional 19 h under 65 psi of hydrogen pressure. The mixture was filtered through a pad of diatomaceous earth, the volatiles were removed from the filtrate under reduced pressure, and the crude tert -butyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate was carried on to the next step without purification. MS (APCI ^- ) m/z 400 [MH] ^- .

[00447] To a solution of crude tert -butyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate in methylene chloride (3 mL) was added trifluoroacetic acid (3 mL). The reaction mixture was stirred for 1 h at room temperature. The volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex ^® Luna ^® C18(2) 5 μm 100 AXIA™ (250 mm x 25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 min at a flow rate of 25 mL/min] to give the trifluoroacetic acid salt of the title compound (80 mg, 0.19 mmol, 47% yield over two steps). MS (APCI ⁺ ) m/z 302 [M+H] ⁺ .

Example 84B: 5-{8-fluoro-6-hydroxy-2-[(pyrrolidin-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00448] The trifluoroacetic acid salt of Example 84A (40 mg, 0.096 mmol) was dissolved in N,N -dimethylformamide (2 mL), followed by the addition of sodium carbonate (28.1 mg, 0.266 mmol). After stirring for 5 min, tert- butyl 2-formylpyrrolidine-1-carboxylate (52.9 mg, 0.266 mmol) and acetic acid (0.038 mL, 0.664 mmol) were added and the mixture was stirred for 5 min at room temperature. Sodium cyanoborohydride (25.0 mg, 0.4 mmol) was then added and the mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the crude tert-butyl 2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]methyl}pyrrolidine-1-carboxylate was carried on to the next step without purification. MS (APCI ^- ) m/z 483 [MH] ^- .

[00449] To a solution of crude tert -butyl 2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]methyl}pyrrolidine-1-carboxylate in methylene chloride (3 mL) was added trifluoroacetic acid (3 mL). The reaction mixture was stirred for 1 h at room temperature. The volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex ^® Luna ^® C18(2) 5 μm 100 AXIA™ (250 mm x 25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) used over 15 min at a flow rate of 25 ml/min] to give the title compound as the trifluoroacetic acid salt (28 mg, 0.056 mmol, 58% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.15 (s, 1H), 6.63 (s, 1H), 4.31-4.27 (m, 1H), 4.26 (s, 2H), 4.19-4.11 (m, 1H), 4.10-4.01 (m, 1H), 3.47-3.32 (m, 4H), 3.28-3.22 (m, 2H), 3.02 (t, J =6.1 Hz, 2H), 2.26-2.13 (m, 1H), 2.05-1.81 (m, 2H), 1.66 (dk, J =12.9, 8.4 Hz, 1H); MS (CIAD ⁺ ) m/z 385 [M+H] ⁺ .

Example 85: 5-{8-fluoro-6-hydroxy-2-[(pyridin-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 184)

[00450] The trifluoroacetic acid salt of Example 84A (40 mg, 0.096 mmol) was dissolved in N,N -dimethylformamide (2 mL), followed by the addition of sodium carbonate (28.1 mg, 0.266 mmol). After stirring for 5 minutes, 2-pyridinecarboxaldehyde (28.4 mg, 0.266 mmol) and acetic acid (0.038 mL, 0.66 mmol) were added and the mixture was stirred for 5 minutes at room temperature. Sodium cyanoborohydride (25.0 mg, 0.4 mmol) was then added. The mixture was stirred at room temperature for two hours. The volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex ^® Luna ^® C18(2) 5 μm 100 AXIA™ (250 mm x 25 mm). A 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used over 15 min at a flow rate of 25 mL/min] to give the title compound as the trifluoroacetic acid salt (21 mg, 0.039 mmol, 41% yield). ¹ H NMR (500 MHz, DMSO-d6) δ ppm 10.30 (s, 1H), 8.72 (ddd, J =4.8, 1.8, 0.9 Hz, 1H), 7.97 (td, J =7.7, 1.8 Hz, 1H), 7.60 (dt, J =7.8, 1.1 Hz, 1H), 7.52 (ddd, J =7.7, 4.9, 1.2 Hz, 1H), 6.64-6.60 (m, 1H), 4.66 (s, 2H), 4.38 (s, 2H), 4.22 (s, 2H), 3.52 (t, J =6.2 Hz, 2H), 3.05 (t, J =6.3 Hz, 2H); MS (CIAD ⁺ ) m/z 393 [M+H] ⁺ .

Example 86: 5-{7-[(2-cyclobutylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 185)

[00451] To a solution of the product of Example 67F (0.05 g, 0.124 mmol) in ethanol (1 mL) was added 2-cyclobutylethan-1-amine (0.018 g, 0.185 mmol). After 30 min, sodium cyanoborohydride (0.009 g, 0.148 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.014 mL, 0.742 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-7-[(2-cyclohexylethyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0378 g, 0.078 mmol, 62.7% yield). MS ( ^APCI ) m/z 488 [M+H] ⁺ .

[00452] To a suspension of 5-{3-(benzyloxy)-7-[(2-cyclobutylethyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0378 g, 0.078 mmol) and pentamethylbenzene (0.023 g, 0.155 mmol) in dichloromethane (1.6 mL) at -78°C was added a solution of boron trichloride (0.465 mL, 0.465 mmol, 1 M in dichloromethane) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), dichloromethane (2 x 2 mL), and acetonitrile (2 x 1 mL), and then dried in a vacuum oven at 50 °C to give the title compound as the HCl salt (0.0320 g, 0.074 mmol, 95% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.16 (s, 1H), 8.99-8.82 (m, 2H), 6.53 (s, 1H), 4.32 (s, 2H), 3.43-3.35 (m, 1H), 3.11 (dd, J =16.0, 5.5 Hz, 1H), 2.94-2.84 (m, 2H), 2.83-2.65 (m, 2H), 2.60 (dd, J = 16.1, 10.1 Hz, 1H), 2.32 (g, J = 7.7 Hz, 1H), 2.24-2.16 (m, 1H), 2.12-1.96 (m, 3H), 1.93-1.57 (m, 7H); MS (CIAD ⁺ ) m/z 398 [M+H] ⁺ .

Example 87: 5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 186)

[00453] To a solution of the product of Example 67F (0.05 g, 0.124 mmol) in ethanol (1 mL) was added 2-aminoethyl isopropyl ether (0.019 g, 0.185 mmol). After 30 min, sodium cyanoborohydride (0.009 g, 0.148 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.014 mL, 0.742 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-[3-(benzyloxy)-1-fluoro-7-({2-[(propan-2-yl)oxy]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0426 g, 0.087 mmol, 70.1% yield). MS ( ^APCI ) m/z 492 [M+H] ⁺ .

[00454] A suspension of 5-[3-(benzyloxy)-1-fluoro-7-({2-[(propan-2-yl)oxy]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0426 g, 0.087 mmol) and 10% palladium hydroxide on carbon (0.085 g, 0.303 mmol, 50 wt % in water) in a mixture of water (0.5 mL) and tetrahydrofuran (5 mL) was stirred for 20.5 h under 160 psi of hydrogen pressure. After filtration, ^Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0204 g, 0.051 mmol, 58.6% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.24 (s, 1H), 8.36 (br. s, 2H), 6.46 (s, 1H), 3.93 (d, J = 1.8 Hz, 2H), 3.62 (dt, J = 8.4, 5.7 Hz, 3H), 3.43-3.34 (m, 1H), 3.18 (k, J = 5.0 Hz, 2H), 3.08 (dd, J =15.8, 5.4 Hz, 1H), 2.80 (dt, J =17.1, 4.4 Hz, 1H), 2.71 (dd, J =17.2, 11.5, 5.5 Hz, 1H), 2.57-2.50 (m, 1H), 2.16 (dd, J =11.0, 5.1 Hz, 1H), 1.68 (cd, J =11.7, 5.3 Hz, 1H), 1.14 (d, J =6.1 Hz, 6H); MS (CIAD ⁺ ) m/z 402 [M+H] ⁺ .

Example 88: 5-{1-fluoro-3-hydroxy-7-[(2-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 187)

[00455] To a solution of the product of Example 67F (0.1 g, 0.247 mmol) in ethanol (2 mL) was added 1-amino-3-methylbutan-2-ol (0.038 g, 0.371 mmol). After 30 min, sodium cyanoborohydride (0.019 g, 0.297 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.028 mL, 1.484 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-1-fluoro-7-[(2-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0583 g, 0.119 mmol, 48% yield). MS ( ^APCI ) m/z 492 [M+H] ⁺ .

[00456] A suspension of 5-{3-(benzyloxy)-1-fluoro-7-[(2-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0583 g, 0.119 mmol) and 5% palladium hydroxide on carbon (0.0201 g, 0.084 mmol, 44.4 wt % in water) in a mixture of N,N -dimethylformamide (0.5 mL), tetrahydrofuran (2 mL), and water (0.5 mL) was stirred for 18 h under 50 psi of hydrogen. After filtration, ^Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0324 g, 0.081 mmol, 68.1% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.22 (br. s, 1H), 8.48 (b. s, 2H), 6.46 (b. s, 1H), 5.28 (b. s, 1H), 3.94 (s, 2H), 3.57-3.49 (m, 2H), 3.45-3.35 (m, 1H), 3.20-3.05 (m, 2H), 2.96-2.65 (m, 3H), 2.66-2.50 (m, 1H), 2.20 (dd, J =29.2, 12.1 Hz, 1H), 1.81-1.60 (m, 2H), 0.91 (d, J =2.8 Hz, 3H), 0.89 (d, J =2.9 Hz, 3H); MS (CIAD ⁺ ) m/z 402 [M+H] ⁺ .

Example 89: 5-{7-[(2-cyclopropyl-2-hydroxyethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 188)

[00457] To a solution of the product of Example 67F (0.1 g, 0.247 mmol) in ethanol (2 mL) was added 2-amino-1-cyclopropylethan-1-ol (0.038 g, 0.371 mmol). After 30 min, sodium cyanoborohydride (0.019 g, 0.297 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.028 mL, 1.484 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-{3-(benzyloxy)-7-[(2-cyclopropyl-2-hydroxyethyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0909 g, 0.186 mmol, 75% yield). MS ( ^APCI ) m/z 490 [M+H] ⁺ .

[00458] A suspension of 5-{3-(benzyloxy)-7-[(2-cyclopropyl-2-hydroxyethyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0909 g, 0.186 mmol) and 5% palladium hydroxide on carbon (0.030 g, 0.125 mmol, 44.4 wt % in water) in a mixture of N,N -dimethylformamide (1 mL) and tetrahydrofuran (2 mL) was stirred for 18 h under 50 psi of hydrogen. After filtration, ^Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0230 g, 0.058 mmol, 31% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.24 (s, 1H), 8.53 (s, 2H), 6.46 (s, 1H), 5.47 (d, J =5.1 Hz, 1H), 3.99-3.88 (m, 2H), 3.52-3.36 (m, 2H), 3.25-2.98 (m, 5H), 2.88-2.67 (m, 1H), 2.62-2.52 (m, 1H), 2.23 (d, J =12.0 Hz, 1H), 2.16 (d, J =12.6 Hz, 1H), 1.84-1.54 (m, 1H), 0.95-0.84 (m, 1H), 0.51-0.41 (m, 2H), 0.35 (ddt, J =8.8, 4.9, 1.8 Hz, 1H), 0.32-0.22 (m, 1H); MS (CIAD ⁺ ) m/z 400 [M+H] ⁺ .

Example 90: 5-(1-fluoro-3-hydroxy-7-{[3-(trimethylsilyl)propyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 189)

[00459] To a solution of the product of Example 67F (0.1 g, 0.247 mmol) in ethanol (2 mL) was added (3-aminopropyl)trimethylsilane (0.049 g, 0.371 mmol). After 30 min, sodium cyanoborohydride (0.019 g, 0.297 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.028 mL, 1.484 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-[3-(benzyloxy)-1-fluoro-7-{[3-(trimethylsilyl)propyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0917 g, 0.176 mmol, 71.4% yield). MS ( ^APCI ) m/z 520 [M+H] ⁺ .

[00460] A suspension of 5-[3-(benzyloxy)-1-fluoro-7-{[3-(trimethylsilyl)propyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0917 g, 0.176 mmol) and 5% palladium hydroxide on carbon (0.049 g, 0.204 mmol, 44.4 wt % in water) in a mixture of N,N -dimethylformamide (1 mL) and tetrahydrofuran (2 mL) was stirred for 18 h under 50 psi of hydrogen. After filtration, Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0271 g, 0.063 mmol, 35.8% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.22 (s, 1H), 8.36 (s, 2H), 6.49-6.44 (m, 18H), 3.93 (s, 2H), 3.56-3.35 (m, 1H), 3.08 (dd, J =16.1, 5.5 Hz, 1H), 3.00 (dd, J =8.9, 6.7 Hz, 2H), 2.85-2.66 (m, 2H), 2.60-2.46 (m, 1H), 2.18-2.10 (m, 1H), 1.75-1.53 (m, 3H), 0.59-0.50 (m, 2H), 0.02 (s, 9H); MS (CIAD ⁺ ) m/z 430 [M+H] ⁺ .

Example 91: 5-[1-fluoro-3-hydroxy-7-({3-[hydroxy(dimethyl)silyl]propyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 190)

[00461] To a solution of the product of Example 67F (0.1 g, 0.247 mmol) in ethanol (2 mL) was added 3-(ethoxydimethylsilyl)propylamine (0.060 g, 0.371 mmol). After 30 min, sodium cyanoborohydride (0.019 g, 0.297 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.028 mL, 1.484 mmol) and then diluted with acetonitrile (2 mL) and water (1 mL). Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-[3-(benzyloxy)-1-fluoro-7-({3-[hydroxy(dimethyl)silyl]propyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0419 g, 0.080 mmol, 16.9% yield). MS ( ^APCI ) m/z 522 [M+H] ⁺ .

[00462] A suspension of 5-[3-(benzyloxy)-1-fluoro-7-({3-[hydroxy(dimethyl)silyl]propyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0419 g, 0.080 mmol) and 5% palladium hydroxide on carbon (0.0143 g, 0.060 mmol, 44.4 wt % in water) in a mixture of N,N -dimethylformamide (2 mL) and tetrahydrofuran (2 mL) was stirred for 18 h under 50 psi of hydrogen. After filtration, Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0205 g, 0.048 mmol, 59.1% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.92 (br s, 1H), 8.91 (br s, 2H), 6.51 (s, 1H), 4.22 (s, 2H), 3.42 (br s, 1H), 3.12 (dd, J = 15.6, 5.5 Hz, 1H), 3.06-2.94 (m, 2H), 2.91-2.71 (m, 1H), 2.62 (dd, J = 16.1, 10.1 Hz, 1H), 2.27-2.15 (m, 1H), 1.78-1.65 (m, 3H), 0.63-0.54 (m, 2H), 0.10 (s, 6H); MS (APCI ⁺ ) m/z 432 [M+H] ⁺ .

Example 92: 5-[8-fluoro-6-hydroxy-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 191)

Example 92A: 5-[6-(benzyloxy)-8-fluoro-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00463] A solution of n -butyl lithium in hexane (2.3 M, 0.24 mL, 0.55 mmol, 2.2 equivalents) was added dropwise to a suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate, the product of Example 54A (nominally 0.25 mmol, 1 equivalent) in tetrahydrofuran (1.5 mL) at 0°C. The reaction vessel was immediately removed from the cooling bath and the mixture was stirred for 10 min at 23°C. 2-Fluoropyridine (0.03 mL, 0.35 mmol, 1.4 equivalents) was added to the reaction mixture at 23 °C, and the resulting mixture was stirred for 30 min at 23 °C. The reaction vessel was then sealed and the sealed vessel was placed in a heating block that was preheated to 60 °C. The reaction mixture was stirred for 19 h at 60 °C. Liquid chromatography - mass spectrometry analysis of the reaction mixture showed that no reaction occurred. The reaction mixture was concentrated. The resulting residue was dissolved in dimethyl sulfoxide (0.6 mL). Additional 2-fluoropyridine (0.06 mL, 0.70 mmol, 2.8 equivalents) was added at 23 °C. The reaction vessel was sealed and the sealed vessel was placed in a heating block preheated to 100 °C. The reaction mixture was stirred for 20 h at 100 °C and then cooled to 23 °C. Additional 2-fluoropyridine (0.06 mL, 0.70 mmol, 2.8 equivalents) and N,N -diisopropylethylamine (0.13 mL, 0.76 mmol, 3.0 equivalents) were added at 23 °C. The reaction vessel was sealed and the sealed vessel was placed in a heating block preheated to 100 °C. The reaction mixture was stirred for 26 h at 100 °C and then cooled to 23 °C. The mixture was diluted with aqueous ammonium hydroxide solution (30% w/v, 1.0 mL) and the diluted mixture was purified by reverse-phase flash column chromatography (100 g RediSep Rf Gold ^® C18 column, elution with a gradient of 10-100% [v/v] methanol - 0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] in 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 60 mL/min). The fractions containing the product were collected and concentrated (~63 mg). The resulting residue was used in the next step without further purification. MS (APCI ⁺ ) m / z 469 [M+H] ⁺ .

Example 92B: 5-[8-fluoro-6-hydroxy-2-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00464] A solution of boron trichloride in dichloromethane (1.0 M, 0.80 mL, 0.80 mmol, 5.95 equivalents) was added to a suspension of the product of Example 92A (nominally 63 mg, 0.13 mmol, 1 equivalent) and pentamethyl benzene (51 mg, 0.34 mmol, 2.6 equivalents) in dichloromethane (1.0 mL) at -78 °C. The reaction mixture was stirred for 2 min at -78 °C. The reaction vessel was then removed from the cooling bath and placed in an ice bath at 0 °C. The reaction mixture was stirred for 20 min at 0 °C. The product mixture was then cooled over 10 min to -78 °C and diluted with ethanol (1.5 mL). The diluted mixture was concentrated under a stream of nitrogen. The resulting residue was triturated with heptanes (2 x 3.0 mL). The resulting residue was dissolved in 25% methanol-acetonitrile (v/v, 7.0 mL) and ethyl acetate (~4 mL) was added slowly. This gave a suspension. The mother liquor was decanted and the resulting residue was triturated with 15% ethyl acetate-40% pentane-45% acetonitrile (v/v/v, 5 mL) to give the title compound (12 mg, 0.032 mmol, 24% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.13 (lat, 1H), 8.08 (dd, J =5.9, 1.9 Hz, 1H), 7.91 (s, 1H), 6.89 (t, J =6.7 Hz, 1H), 6.67 (s, 1H), 4.67 (s, 2H), 4.23 (s, 2H) 3.84 (t, J =5.8 Hz, 1H), 2.90 (t, J =5.8 Hz, 1H); MS (CIBP ⁺ ) m / z 379 [M+H] ⁺ .

Example 93: 5-{2-[2-(3,3-difluorocyclobutyl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 192)

Example 93A: 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt

[00465] A vial containing a suspension of tert -butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2( 1H )-carboxylate (0.125 g, 0.254 mmol, Example 44H) in dichloromethane (0.85 mL) was cooled to 0 °C. 2,2,2-Trifluoroacetic acid (0.20 mL, 2.5 mmol) was then added dropwise and the cooling bath was subsequently removed. After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (3 x 3 mL) to give the title compound. This material was used without further purification. MS (CIAD ⁺ ) m/z 433.4 [M+CH ₃ CN+H] ⁺ .

Example 93B: 5-{6-(benzyloxy)-2-[2-(3,3-difluorocyclobutyl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00466] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trionetrifluoroacetate (theoretical 0.254 mmol, Example 93A) were added potassium carbonate (0.176 g, 1.27 mmol) and acetonitrile (0.64 mL). A solution of 2-(3,3-difluorocyclobutyl)ethyl 4-methylbenzenesulfonate (0.111 g, 0.381 mmol, Example 93D) in a minimum volume of acetonitrile (approximately 0.050 mL) was then added. The vial was capped and the mixture was heated to 60°C. After 18 h, the reaction mixture was cooled to ambient temperature and filtered through a short pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography [4 g column, gradient of 0-20% methanol in dichloromethane then 50% methanol in dichloromethane] to give the title compound (0.073 g, 0.14 mmol, 56% yield over two steps). MS ( ^APCI ) m/z 510.5 [M+H] ⁺ .

Example 93C: 5-{2-[2-(3,3-difluorocyclobutyl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00467] To a 20 mL Barnstead Hast C reactor containing 10% palladium hydroxide on carbon (0.140 g, 0.498 mmol) were added 55-{6-(benzyloxy)-2-[2-(3,3-difluorocyclobutyl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl} ^-1λ6,2,5 -thiadiazolidine-1,1,3-trione (0.071 g, 0.14 mmol, Example 93B) and tetrahydrofuran (6 mL). The resulting mixture was stirred at ambient temperature for 21.2 h under a hydrogen atmosphere at >160 psi. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and purified by preparative reverse-phase HPLC [Waters XBridge™ RP18, 5 μm, 30×100 mm column, 40 mL/min, 5-70% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)]. Fractions containing the product were combined and concentrated under reduced pressure. The residue was passed through an SCX-2 cartridge (loaded and eluted first with methanol/dichloromethane (1:1), then eluted with 2 M ammonia in methanol) to afford the title compound (0.018 mg, 0.043 mmol, 31% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm 9.37 (br s, 1H), 7.07 (br s, 1H), 6.48 (s, 1H), 3.91 (s, 2H), 3.80 (br s, 2H), 2.98 (br s, 2H), 2.84-2.75 (br m, 4H), 2.71-2.57 (m, 2H), 2.37-2.16 (m, 2H), 2.16-1.98 (m, 1H), 1.79 (q, J = 7.6 Hz, 2H); MS (APCI ⁺ ) m/z 420.3 [M+H] ⁺ .

Example 93D: 2-(3,3-difluorocyclobutyl)ethyl 4-methylbenzenesulfonate

[00468] A vial containing a solution of 2-(3,3-difluorocyclobutyl)ethanol (0.340 g, 2.50 mmol) and triethylamine (0.45 mL, 3.2 mmol) in dichloromethane (12.5 mL) was cooled to 0 °C. 4-Methylbenzenesulfonic anhydride (0.978 g, 3.00 mmol) was then added in one portion and the cooling bath was subsequently removed. After 18 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended in diethyl ether (100 mL) and washed successively with 1 M hydrochloric acid (75 mL), saturated aqueous sodium bicarbonate (75 mL), and brine. The organic phase was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [4 g column, gradient of 0-50% ethyl acetate in heptanes then 100% ethyl acetate] to give 2-(3,3-difluorocyclobutyl)ethyl 4-methylbenzenesulfonate (0.595 g, 2.05% mmol, 82% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 7.83-7.75 (m, 2H), 7.39-7.33 (m, 2H), 4.01 (t, J = 6.1 Hz, 2H), 2.69-2.55 (m, 2H), 2.46 (s, 3H), 2.24-2.05 (m, 3H), 1.88-1.80 (m, 2H).

Example 94: 5-{8-fluoro-6-hydroxy-2-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 193)

Example 94A: 5-{6-(benzyloxy)-8-fluoro-2-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00469] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.254 mmol, Example 93A) were added acetonitrile (0.85 mL), potassium carbonate (0.176 g, 1.27 mmol), and 1-(2-bromoethyl)pyrrolidine hydrobromide (0.099 g, 0.38 mmol). The vial was capped and the mixture was heated to 60°C. After 22 h, a second portion of 1-(2-bromoethyl)pyrrolidine hydrobromide (0.099 g, 0.38 mmol) was added. After a total reaction time of 42 h, the mixture was cooled to ambient temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was partially purified by silica gel chromatography [4 g column, gradient 0-40% methanol (containing 1% ammonium hydroxide) in dichloromethane] to give the title compound (0.066 g, 0.14 mmol) along with some impurities. This material was used without further purification. MS ( ^APCI ) m/z 488.4 [M+H] ⁺ .

Example 94B: 5-{8-fluoro-6-hydroxy-2-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00470] To a 20 mL Barnstead Hast C reactor containing 10% palladium hydroxide on carbon (0.120 g, 0.427 mmol) were added impure 5-{6-(benzyloxy)-8-fluoro-2-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.066 g, 0.14 mmol) and tetrahydrofuran (2 mL). The resulting mixture was stirred at ambient temperature for 20.6 h under a hydrogen atmosphere at 110 psi. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and purified by preparative reverse phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30 x 100 mm, flow rate 40 mL/min, 5-70% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)]. Fractions containing the product were combined and concentrated under reduced pressure. The residue was passed through an SCX-2 cartridge (loaded and eluted first with methanol/dichloromethane (1:1), then eluted with 2 M ammonia in methanol) to afford the title compound (9.0 mg, 0.020 mmol, 8% yield over three steps) in approximately 90% purity as determined by ¹ H NMR analysis. ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm 9.25 (s, 1H), 6.47 (s, 1H), 3.95 (s, 2H), 3.55 (s, 2H), 3.35 (t, J = 5.8 Hz, 2H), 3.27 (t, J = 6.7 Hz, 4H), 2.78 (2 overlapping multiplets, 4H), 2.71 (t, J = 5.8 Hz, 2H), 1.96-1.88 (m, 4H); MS (APCI ⁺ ) m/z 399.4 [M+H] ⁺ .

Example 95: 5-{2-[2-(3,5-dimethyl-1H- pyrazol -4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 194)

Example 95A: 5-{6-(benzyloxy)-2-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00471] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.407 mmol, Example 93A) were added acetonitrile (1.0 mL), potassium carbonate (0.281 g, 2.04 mmol), and 4-(2-bromoethyl)-3,5-dimethyl- 1H- pyrazole (0.124 g, 0.611 mmol). The vial was capped and the mixture was heated to 60°C. After 14 h, a second portion of 4-(2-bromoethyl)-3,5-dimethyl- 1H- pyrazole (0.124 g, 0.611 mmol) was added along with additional potassium carbonate (0.141 g, 1.02 mmol). After 62 h total reaction time, the reaction mixture was cooled to ambient temperature, diluted with dichloromethane, and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was first purified by silica gel chromatography [12 g column, 0-50% gradient of methanol in dichloromethane] and then by reversed phase chromatography [12 g column ^Biotage® Sfär C18 Duo 100 Å 30 μm, gradient of 10-100% methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.070 g, 0.14 mmol, 34% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.01 (br s, 1H), 7.51 (dd, J = 8.1, 6.4 Hz, 2H), 7.40-7.26 (2 overlapping multiplets, 3H), 6.88 (s, 1H), 5.16 (s, 2H), 4.29 (s, 2H), 3.97 (s, 2H), 3.43 (br s, 2H), 3.12 (t, J = 8.4 Hz, 2H), 3.04 (t, J = 6.1 Hz, 2H), 2.77 (dd, J = 10.5, 6.3 Hz, 2H), 2.14 (s, 6H); MS (APCI ⁾ m/z 514.4 [M+H] ⁺ .

Example 95B: 5-{2-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00472] To a 20 mL Barnstead Hast C reactor containing 10% palladium hydroxide on carbon (0.037 g, 0.13 mmol) were added 5-{6-(benzyloxy)-2-[2-(3,5-dimethyl- 1H- pyrazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.067 g, 0.13 mmol, Example 95A) and tetrahydrofuran (4 mL). The resulting mixture was stirred at ambient temperature for 20 h under a hydrogen atmosphere at 60 psi. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography [30 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with dry ice)] to give the title compound (0.023 g, 0.054 mmol, 42% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 12.04 (s, 1H), 9.64 (s, 1H), 6.57 (s, 1H), 4.24 (s, 2H), 3.95 (s, 2H), 3.36 (br s, 2H), 3.10 (t, J = 8.2 Hz, 2H), 2.99 (t, J = 6.2 Hz, 2H), 2.74 (dd, J = 10.1, 6.7 Hz, 2H), 2.13 (s, 6H); MS (APCI ⁺ ) m/z 424.1 [M+H] ⁺ .

Example 96: N- [8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-3-methylbutanimidamide (Compound 195)

[00473] To a solution of the product of Example 67F (0.2 g, 0.495 mmol) in ethanol (4 mL) was added ammonium acetate (0.0762 g, 9.89 mmol). After 30 min, sodium cyanoborohydride (0.037 g, 0.148 mmol) was added as a solid. After 16 h, the reaction mixture was diluted with acetonitrile (2 mL) and water (1 mL). ^Celite® (2 g) was added and the mixture was concentrated in vacuo to give a white powder. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give 5-[7-amino-3-(benzyloxy)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0771 g, 0.190 mmol, 38.5% yield). MS (APCI ⁾ m/z 406 [M+H] ⁺ .

[00474] To a solution of 5-[7-amino-3-(benzyloxy)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.0340 g, 0.084 mmol) and methyl 3-methylbutanecarboximidate hydrochloride (0.019 g, 0.126 mmol) in N,N -dimethylformamide (0.7 mL) was added N,N -diisopropylamine (0.044 mL, 0.252 mmol) at 0 °C. After complete addition, the reaction mixture was heated to 60 °C. After 17 h, the reaction mixture was cooled to room temperature and directly purified by loading onto a Teledyne ISCO 50 g reversed phase C18 column and eluting with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give N -[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-3-methylbutanimidamide (0.0300 g, 0.061 mmol, 73.2% yield). MS (APCI ⁺ ) m/z 489 [M+H] ⁺ .

[00475] To a suspension of N -[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-3-methylbutanimidamide (0.0300 g, 0.061 mmol) and pentamethylbenzene (0.018 g, 0.123 mmol) in dichloromethane (1.2 mL) at -78°C was added a solution of boron trichloride (0.368 mL, 0.368 mmol, 1 M in dichloromethane) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), dichloromethane (2 x 2 mL), and acetonitrile (2 x 1 mL), then dried in a vacuum oven at 50 °C to give the title compound (0.0126 g, 0.032 mmol, 51.5% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.11 (lat s, 4H), 6.47 (s, 1H), 3.97-3.90 (m, 2H), 3.92-3.83 (m, 1H), 3.00 (dd, J =16.1, 5.3 Hz, 1H), 2.86-2.72 (m, 2H), 2.45 (dd, J =16.1, 9.1 Hz, 1H), 2.27 (d, J =7.6 Hz, 2H), 2.02 (hept, J =7.0 Hz, 1H), 1.98-1.91 (m, 1H), 1.72 (dtd, J =12.4, 9.9, 6.2 Hz, 1H), 0.92 (d, J =6.5 Hz, 6H); MS (CIAD ⁺ ) m/z 399 [M+H] ⁺ .

Example 97: 5-{8-fluoro-6-hydroxy-2-[3-(oxan-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 196)

Example 97A: 5-{6-(benzyloxy)-8-fluoro-2-[3-(oxan-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00476] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trionetrifluoroacetate (theoretical 0.10 mmol, Example 93A) were added potassium carbonate (0.070 g, 0.51 mmol) and acetonitrile (0.26 mL). Then 4-(3-bromopropyl)tetrahydro- 2H -pyran (0.032 g, 0.15 mmol) dissolved in a minimum volume of acetonitrile (approximately 0.050 mL) was added. The vial was capped and the mixture was heated to 60 °C. After 18 hours, the reaction mixture was cooled to ambient temperature and filtered through a thin pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography [4 g column, gradient of 0-20% methanol in dichloromethane then 50% methanol in dichloromethane] to give the title compound (0.050 g, 0.096 mmol, 94% yield over two steps). ¹ H NMR (600 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.51-7.45 (m, 2H), 7.38-7.31 (m, 2H), 7.31-7.27 (m, 1H), 6.81 (s, 1H), 5.12 (s, 2H), 3.97 (s, 2H), 3.92 (br s, 2H), 3.81 (ddd, J =11.6, 4.5, 1.8 Hz, 2H), 3.26 (td, J =11.7, 2.1 Hz, 2H), 3.08 (lat s, 2H), 2.91 (lat s, 4H), 1.69-1.60 (m, 2H), 1.57 (dd, J = 12.4, 1.7 Hz, 2H), 1.51-1.43 (m, 1H), 1.23 (q, J = 7.3 Hz, 2H), 1.17-1.08 (m, 2H); MS (APCI ⁺ ) m/z 518.4 [M+H] ⁺ .

Example 97B: 5-{8-fluoro-6-hydroxy-2-[3-(oxan-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00477] To a 20 mL Barnstead Hast C reactor containing 10% palladium hydroxide on carbon (0.100 g, 0.356 mmol) were added 5-{6-(benzyloxy)-8-fluoro-2-[3-(oxan-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.100 g, 0.193 mmol) and tetrahydrofuran (4 mL). The resulting mixture was stirred at ambient temperature for 22.1 h under a hydrogen atmosphere at 60 psi. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography [4 g column, gradient of 0-50% methanol (containing 1% ammonium hydroxide) in dichloromethane]. Fractions containing the product were combined and concentrated under reduced pressure. The residue was passed through an SCX-2 cartridge (loaded and eluted first with methanol/dichloromethane (1:1), then eluted with 2 M ammonia in methanol) to give the title compound (0.035 mg, 0.082 mmol, 42% yield). ¹ H NMR (500 MHz, pyridine -d ₅ ) δ ppm. 6.80 (s, 1H), 4.63 (s, 2H), 4.05 (s, 2H), 3.97 (dd, J =10.7, 3.4 Hz, 2H), 3.33 (td, J =11.7, 2.1 Hz, 2H), 3.11 (t, J =5.9 Hz, 2H), 2.96 (t, J =6.0 Hz, 2H), 2.87 (dd, J =9.0, 6.6 Hz, 2H), 1.73 (tt, J =10.1, 6.6 Hz, 2H), 1.50 (ddd, J =12.6, 3.9, 1.8 Hz, 2H), 1.38 (dtk, J =14.6, 7.0, 3.4 Hz, 1H), 1.29-1.19 (m, 3H), 1.21-1.14 (m, 1H); MS (CIAD ⁺ ) m/z 428.4 [M+H] ⁺ .

Example 98: 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 197)

Example 98A: 5-[3-(benzyloxy)-1-fluoro-7-(3-hydroxy-3-methylbutoxy)naphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3- trion

[00478] A mixture of the product of Example 1H (100 mg, 0.249 mmol), 4-bromo-2-methylbutan-2-ol (49.8 mg, 0.298 mmol) and _Cs2CO3 (162 mg, 0.497 mmol) in N,N -dimethylformamide (1 mL) was stirred at ambient temperature for 14 h. The mixture was diluted _with ethyl acetate and 0.2 N HCl (15 mL). The organic layer was separated, washed with brine, dried over _Na2SO4 and concentrated to give the title _compound , which was used in the next step without further purification. MS (APCI ^- ) m/z 487.5 [MH] ^- .

Example 98B: 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00479] A solution of the product of Example 98A (120 mg, 0.246 mmol) in tetrahydrofuran (6 mL) was added to a 20 mL Barnstead Hastelloy C reactor charged with 5% wet Pd/C (145 mg, 0.681 mmol). The mixture was stirred under 150 psi of hydrogen for 25 h at 25 °C. The reaction mixture was filtered, the filtrate was concentrated and the residue was triturated with dichloromethane to give the title compound (65 mg, 0.163 mmol, 66% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.22 (s, 1H), 7.70 (dd, J =9.1, 1.5 Hz, 1H), 7.22 (d, J =2.5 Hz, 1H), 7.16 (dd, J =9.0, 2.6 Hz, 1H), 7.06 (s, 1H), 4.45 (s, 2H), 4.19 (t, J =7.2 Hz, 2H), 1.90 (t, J =7.2 Hz, 2H), 1.19 (s, 6H); MS (CIAD ^- ) m/z 397.7 [MH] ^- .

Example 98C: 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00480] A solution of the product of Example 98B (118 mg, 0.296 mmol) in acetic acid (4 mL) was added to a 20 mL Barnstead Hastelloy C reactor charged with 10% palladium hydroxide on carbon (120 mg, 0.427 mmol). The mixture was stirred under 182 psi of hydrogen at 25°C for 20 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm, 25×150 mm column, flow rate 80 mL/min, gradient of methanol in 0-50% buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (49 mg, 0.117 mmol, yield 39%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.91 (lat s, 1H), 7.20 (lat s, 4H), 6.41 (lat s, 1H), 4.20 (s, 1H), 3.94 (s, 2H), 3.70 (m, 1H), 3.57 (m, 2H), 2.77 (m, 2H), 2.46-2.61 (m, 2H), 1.70-1.87 (m, 2H), 1.65 (t, J =8 Hz, 2H), 1.09 (s, 6H); MS (IER ^- ) m/z 401 [MH] ^- .

Example 99: 5-[(7 R )-7-amino-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 198)

Example 99A: 7' - bromo-8' - fluoro-6 ' -[(2-methoxyethoxy)methoxy]-3 ',4' - dihydro- 1'H-spiro[[1,3]dioxolane-2,2' - naphthalene]

[00481] To a solution of 2,2,6,6-tetramethylpiperidine (4.35 mL, 25.6 mmol) in tetrahydrofuran (50 mL) at <2 °C (internal temperature) was added a solution of n -butyl lithium (9.61 mL, 24.01 mmol, 2.5 M in hexanes) slowly (internal temperature <7 °C). The reaction mixture was stirred for 30 min, then cooled to an internal temperature of <-75 °C. A solution of the product of Example 22D (5.00 g, 16.01 mmol) in tetrahydrofuran (25.00 mL) was added slowly down the side of the flask (internal temperature <-67 °C), followed by N,N,N ',N' -tetramethylethylenediamine (3.62 mL, 24.01 mmol). The reaction mixture was stirred for 90 min while maintaining the internal temperature below -75 °C, then a solution of 1,2-dibromotetrachloroethane (7.82 g, 24.01 mmol) in tetrahydrofuran (12.50 mL) was slowly added down the center of the flask (internal temperature < -65 °C). After complete addition, the reaction mixture was stirred for 5 min and then the cooling bath was removed. After reaching 10 °C, the reaction mixture was quenched with 50% 1.0 M aqueous sodium thiosulfate - saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL, 2 x 25 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated to ∼80 mL total volume. Silica gel (∼10 g) was added and the mixture was concentrated to give a powder. The resulting residue was purified by flash column chromatography (120 g RediSep Rf Gold ^® silica gel column, eluting with a gradient of 0-50% ethyl acetate to 0.1% triethylamine-heptanes to give the title compound (4.89 g, 12.50 mmol, 78% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 6.79 (br s, 1H), 5.30 (s, 2H), 4.07-3.99 (m, 4H), 3.87-3.82 (m, 2H), 3.58-3.53 (m, 2H), 3.38 (s, 3H), 2.97-2.91 (t, J = 6.7 Hz, 2H), 2.88 (s, 2H), 1.92 (t, J = 6.7 Hz, 2H).

Example 99B: 7-bromo-8-fluoro-6-[(2-methoxyethoxy)methoxy]-3,4-dihydronaphthalen-2(1H)-one

[00482] The product of Example 99A (4.74 g, 12.12 mmol, 1 equivalent) was suspended in 88% formic acid (w/v, 26.0 mL, 606.0 mmol, 50.0 equivalents) at 23 °C and stirred for 20 minutes. The product mixture was then carefully poured into a stirred mixture of saturated aqueous sodium bicarbonate (350 mL) and ethyl acetate (400 mL) at 23 °C. The resulting biphasic mixture was stirred for 20 minutes at 23 °C. The mixture was then transferred to a separatory funnel and the resulting layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined and the combined organic layers were washed successively with saturated aqueous sodium bicarbonate solution (6 x 100 mL), water (100 mL), and saturated aqueous sodium chloride solution (100 mL). The washed organic layer was dried over magnesium sulfate. The dried solution was filtered through a diatomaceous earth plug (2.0 cm x 8.0 cm). The filter cake was washed with ethyl acetate (50 mL). The filtrates were combined and concentrated. The resulting residue was reconcentrated from ether (15 mL) and once from pentane (15 mL) to give the title compound (4.18 g, 12.0 mmol, 99% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 6.91 (s, 1H), 5.35 (s, 2H), 3.91-3.86 (m, 2H), 3.60-3.52 (m, 4H), 3.38 (s, 3H), 3.09-2.99 (m, 2H), 2.62-2.56 (m, 2H).

Example 99C: (2R)-7-bromo-8-fluoro-6-[(2-methoxyethoxy)methoxy]-N-[(1S)-1-(naphthalen-1-yl)ethyl]-1,2,3,4-tetrahydronaphthalen-2-amine

[00483] A 250 mL round bottom flask was charged with the product from Example 99B (3.84 g, 11.06 mmol, 1 equivalent) and deoxygenated methanol (pre-flushed with nitrogen for 30 min, 110 mL). The reaction vessel was then sealed with a rubber septum. The reaction mixture was further deoxygenated by briefly applying vacuum (10-20 s) and backfilling with nitrogen (×2). ( S )-1-(Naphthalen-1-yl)ethanamine (1.86 g, 11.06 mmol, 1.0 equivalent) was then added dropwise to the solution under nitrogen at 23 °C. A dark red mixture was obtained. The reaction vessel was then placed on a heating block that had been preheated to 70 °C and stirred for 1 hour. A clear orange solution formed within 30 min. The block temperature was then increased to 80 °C with continued stirring for an additional 2 h. Additional ( S )-1-(naphthalen-1-yl)ethanamine (330 mg, 1.93 mmol, 0.2 equivalents) was added at 80 °C with continued stirring for an additional 1 h. The reaction mixture was then placed in a -20 °C cooling bath (brine to ice) and stirred for 20 min. The reaction vessel was opened briefly and sodium borohydride (1.26 g, 33.20 mmol, 3.0 equivalents) was added to the suspension in one portion at -20 °C. The reaction vessel was recapped and the reaction mixture was stirred for 30 min at -20 °C. The product mixture was then diluted successively with saturated aqueous ammonium chloride solution (50 mL), water (50 mL), and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, and the combined organic layers were washed with brine (2 x 75 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered through a diatomaceous earth plug (2.0 cm x 8.0 cm). The filter cake was washed with ethyl acetate (50 mL). The filtrates were combined and concentrated. The resulting residue was dissolved in 75% dichloromethane-ethyl acetate (100 mL). Diatomaceous earth (11 g) was added to the solution, and the mixture was concentrated. The resulting residue was purified by flash column chromatography (RediSep Rf ^Gold® 120 g silica gel column, eluting with a gradient of 0-10% methanol-dichloromethane). The fractions containing the product were collected and the combined fractions were concentrated. The resulting residue was dissolved in dichloromethane (100 mL). Diatomaceous earth (24 g) was added to the solution and the mixture was concentrated. The resulting residue was re-concentrated from pentane (100 mL). The resulting residue was purified by flash column chromatography (RediSep Rf ^Gold® 120 g silica column, eluting with a gradient of 0 to 80% ethyl acetate-heptanes, then 80 to 100% ethyl acetate-heptanes) to afford the title compound (2.87 g, 5.70 mmol, 52% yield). MS (CIBP ⁺ ) m / z 502 [M+H] ⁺ .

Example 99D: tert-butyl {[(7R)-1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-{[(1S)-1-(naphthalene-1-yl)ethyl]amino}-5,6,7,8 -tetrahydronaphthalene-2-yl]amino}acetate

[00484] A 250 mL round bottom flask was charged with a solution of the product of Example 99C (2.87 g, 5.71 mmol, 1 equivalent) in 1,4-dioxane (60 mL) and tert -butyl glycinate (1.2 mL, 8.78 mmol, 1.5 equivalents), BrettPhos (61 mg, 0.11 mmol, 2.0 mol %), BrettPhos Pd G3 (104 mg, 0.11 mmol, 2.0 mol %) and cesium carbonate (5.58 g, 17.13 mmol, 3.0 equivalents). The reaction vessel was equipped with a reflux condenser and a rubber septum. The reaction mixture was briefly placed under vacuum (5-15 seconds) and backfilled with nitrogen (×5). The reaction vessel was then placed in a heating block preheated to 100 °C. The reaction mixture was stirred for 14 h at 100 °C and then cooled to 23 °C over 30 min. Additional BrettPhos Pd G3 (146 mg, 0.16 mmol, 2.8 mol %) was added. The reaction mixture was sealed and deoxygenated with nitrogen as above (×5). The reaction vessel was then placed in a heating block preheated to 100 °C. The reaction mixture was stirred for 4 h at 100 °C and then cooled to 23 °C over 30 min. Additional BrettPhos Pd G3 (110 mg, 0.11 mmol, 2.0 mol %) was added. The reaction mixture was sealed and deoxygenated with nitrogen as above (×5). The reaction vessel was then placed in a heating block preheated to 100 °C. The reaction mixture was stirred for 16 h at 100 °C and then cooled to 23 °C over 30 min. The cooled mixture was poured into a stirred mixture of saturated aqueous ammonium chloride (100 mL) and ethyl acetate (300 mL). The resulting biphasic mixture was stirred for 10 min. The mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride (100 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was dissolved in ethyl acetate (100 mL). Diatomaceous earth (25 g) was added to the solution and the mixture was concentrated. The resulting residue was purified by flash column chromatography (RediSep Rf ^Gold® silica column, 120 g, eluting with a gradient of 0 to 80% ethyl acetate-heptanes, then 80 to 100% ethyl acetate-heptanes) to afford the title compound (2.32 g, 4.2 mmol, 74% yield). MS ( ^APCI ) m / z 553 [M+H] ⁺ .

Example 99E: tert-butyl ({(7R)-7-amino-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthalen-2-yl}amino)acetate

[00485] A suspension of the product of Example 99D (2.32 g, 4.20 mmol, 1 equivalent) and 10% palladium hydroxide on carbon (1.30 g, 4.6 mmol, 1.1 equivalent, 50% wet) in tetrahydrofuran (50 mL) was stirred in a stainless steel Parr reactor under hydrogen atmosphere (50 psi) for 34 h at 23 °C. The product mixture was then filtered and the filtrate was concentrated. The resulting residue was used in the next step without further purification. MS (APCI ⁺ ) m / z 399 [M+H] ⁺ .

Example 99F: tert-butyl ({(7R)-7-[(tert-butoxycarbonyl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthalene-2-yl}amino)acetate

[00486] 4-Dimethylaminopyridine (56 mg, 0.46 mmol, 12.3 mol %) was added to a solution of the product of Example 99E (nominal 3.73 mmol, 1 equivalent) and di- tert -butyl dicarbonate (900 mg, 4.12 mmol, 1.1 equivalents) in dichloromethane (20 mL) at 23 °C. The reaction mixture was stirred for 16 h at 23 °C. The mixture was successively diluted with saturated aqueous ammonium chloride (30 mL), water (50 mL), and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (2 x 75 mL). The organic layers were combined, and the combined organic layers were washed with saturated aqueous sodium chloride (50 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (RediSep Rf Gold ^® 80 g silica gel column, eluting with a gradient of 0 to 100% ethyl acetate-heptanes) to afford the title compound (1.57 g, 3.15 mmol, 84% yield, two steps). MS (APCI ⁺ ) m / z 499 [M+H] ⁺ .

Example 99G: tert-butyl [{(7R)-7-[(tert-butoxycarbonyl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthalen-2-yl}({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]acetate

[00487] Allyl alcohol (0.28 mL, 4.07 mmol, 1.5 equivalents) was added dropwise to a solution of chlorosulfonyl isocyanate (0.35 mL, 4.07 mmol, 1.5 equivalents) in dichloromethane (6 mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. A solution of the product of Example 99F (1.35 g, 2.71 mmol, 1 equivalent) and N,N -diisopropylethylamine (0.95 mL, 5.42 mmol, 2.0 equivalents) in dichloromethane (5 mL) was then slowly added through the side of the flask at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and then diluted with water (5 mL). The mixture was then transferred to a separatory funnel and the resulting layers were separated. The aqueous layer was extracted with dichloromethane (2 x 10 mL). The organic layers were combined, and the combined organic layers were washed with aqueous sodium bisulfate solution (1.0 M, 10 mL). The combined aqueous layers were re-extracted with dichloromethane (3 x 5 mL). The organic layers were combined, and the combined organic layers were washed with brine (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The resulting residue was used without further purification.

Example 99H: tert-butyl [(2R)-8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

[00488] A solution of tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.08 mmol, 3.0 mol %), the product of Example 99G (nominally 2.71 mmol, 1 equivalent), and sodium methoxide (25 wt % in methanol, 3.8 mL, 16.5 mmol, 6.1 equivalents) in methanol (30 mL) was deoxygenated by briefly applying vacuum and backfilling with nitrogen (×3). The reaction vessel was then placed in a heating block preheated to 70 °C. The reaction mixture was stirred for 1.5 h at 70 °C. The product mixture was then cooled to 23 °C. The cooled product mixture was concentrated. The concentrated mixture was dissolved in 16% acetonitrile-ethyl acetate (v/v, 60 mL) and aqueous hydrochloric acid (1.0 M, 25.0 mL). The resulting biphasic mixture was stirred for 5 min. Then, the biphasic mixture was transferred to a separatory funnel and the resulting layers were separated. The aqueous layer was extracted with 10% acetonitrile-ethyl acetate (v/v, 3 × 15 mL). The organic layers were combined, and the combined organic layers were washed with brine (2 × 5 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered through a pad of diatomaceous earth (2.0 cm × 6.0 cm). Diatomaceous earth (~15 g) was added to the filtrates, and the mixture was concentrated. The resulting residue was purified by reverse-phase flash column chromatography (275 g RediSep Rf Gold ^® C18 column, eluting with a gradient of 5-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 125 mL/min, λ = 214, 254) to give the title compound (900 mg, 1.78 mmol, 66% yield, two steps). MS (APCI ⁺ ) m / z 404 [M + HC(O)OC(CH ₃ ) ₃ ] ⁺ .

Example 99I: 5-[(7R)-7-amino-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione, hydrochloride salt

[00489] A solution of hydrogen chloride in dioxane (4.0 M, 0.1 mL, 0.40 mmol, 6.1 equivalents) was added to a solution of the product of Example 99H (33.0 mg, 0.066 mmol, 1 equivalent) in acetonitrile (0.2 mL) at 23 °C. A precipitate formed immediately. The reaction mixture was stirred for 1 h at 23 °C. The reaction mixture was then diluted with ether (1.0 mL) and additional precipitate formed immediately. The precipitate was allowed to settle and the supernatant was removed. The resulting residue was triturated with 10% acetonitrile-ethyl acetate (v/v, 3 x 1.0 mL). ¹ H NMR analysis of the residue thus obtained indicated the presence of starting material. The residue was suspended in a solution of hydrogen chloride in dioxane (4.0 M, 0.4 mL, 1.60 mmol, 24.2 equivalents) at 23 °C. The reaction mixture was stirred for 4 h at 23 °C. Then the product mixture was concentrated to give the title compound (21.0 mg, 0.060 mmol, 91% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 997 (lat, 1H), 6.51 (s, 1H), 4.24 (s, 2H), 3.76-3.63 (m, 1H), 3.01 (dd, J =16.0, 5.5 Hz, 1H), 2.86-2.72 (m, 2H), 2.11-2.01 (m, 1H), 1.77-1.64 (m, 1H); MS (CIBP ⁺ ) m / z 316 [M+H] ⁺ .

Example 100: 5-{(7 R )-7-[(4,4-difluorobutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 199)

[00490] The product of Example 67 (0.3470 g, 0.782 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a CO ₂ pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical CO ₂ supplied by a 350 psi dewar of bone dry non-certified CO ₂ with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (90:10) at a concentration of 10 mg/mL. The sample was loaded into the modifier stream in 0.4 mL (4 mg) injections. The mobile phase was maintained isocratically at 35% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a CHIRALPAK® IC column with 21 mm × 250 mm i.d. and 5 μm particles. The enantiomer peak eluted early to give the title compound (0.1043 g, 0.256 mmol, 65.5% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm (J = 7.6, Hz, 10.3 ... 9.18 (s, 1H), 8.35 (s, 2H), 6.44 (s, 1H), 6.12 (tt, J =56.6, 4.2 Hz, 1H), 3.90 (s, 2H), 3.09-2.99 (m, 3H), 2.82-2.63 (m, 2H), 2.10 (d, J =12.0 Hz, 1H), 2.00-1.82 (m, 2H), 1.66 (ddt, J =27.2, 11.2, 6.7 Hz, 3H); MS (CIAD ⁺ ) m/z 408 [M+H] ⁺ .

Example 101: 5-{(7 R )-7-[(2-cyclopentylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 200)

Example 101A: 6-(benzyloxy)-7-bromo-8-fluoro-3,4-dihydronaphthalene-2(1H)-one

[00491] The product of Example 67B (33.31 g, 73.1 mmol) was suspended in 88% formic acid (70 mL). After 1.5 h, the mixture was diluted with water (400 mL). The resulting solid was collected by filtration, washed with water (800 mL), and dried in a vacuum oven at 30 °C to give the title compound (26.84 g, 71.7 mmol, 98% yield) as a monohydrate. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 7.49 (ddt, J =7.7, 1.4, 0.7 Hz, 2H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.09-7.05 (m, 1H), 5.23 (s, 2H), 3.50 (d, J =1.1 Hz, 2H), 3.08-3.01 (m, 2H), 2.48 (s, 2H).

Example 101B: ( 2R )-6-(benzyloxy)-7-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalene-2-aminohydrochloride

[00492] To a solution of sodium phosphate monobasic (38.2 g, 318 mmol) in water (0.95 L) was added concentrated hydrochloric acid (175 mL), followed by the portionwise addition of sec -butylamine (235 mL, 2326 mmol). The pH was adjusted to 6.5 by the addition of concentrated hydrochloric acid. After cooling the mixture to 30 °C, pyridoxal 5-phosphate (0.625 g, 286 mmol) was added and 100 mL of the buffer solution was removed for use below. To the remaining buffer solution was slowly added a solution of the product of Example 101A (118 g, 338 mmol) in dimethyl sulfoxide (0.95 L), maintaining the pH between 7.25 and 7.75 by the addition of either concentrated hydrochloric acid or a 50% aqueous solution of sec -butylamine. After complete addition, a dispersion of ^Codexis® ATA-025 (12 g) in 100 mL of the above buffer was added and the resulting mixture was heated to 40 °C, maintaining the pH between 7.25 and 7.75 by adding either concentrated hydrochloric acid or 50% aqueous sec -butylamine. After 24 h, the reaction mixture was cooled to 10 °C and filtered. The solid was triturated with water (2 x 250 mL) and then acetonitrile (2 x 250 mL) and then dried in a vacuum oven at 40 °C to give the title compound (126 g, 91% activity by HPLC, 327 mmol, activity corrected yield 96.9%). Analytical HPLC conditions: Column Supelco ^Acentis® Express C18, 4.6 x 150 mm, 2.7 micron, held at 35°C, eluting with a gradient of 30 to 90% acetonitrile in 0.1% perchloric acid in water over 6 min, holding at 90% acetonitrile for 1 min then back to 30% acetonitrile for 0.1 min; ¹ H NMR (500 MHz, CD ₃ OD) δ ppm 7.50-7.44 (m, 2H), 7.41-7.34 (m, 2H), 7.34-7.27 (m, 1H), 6.78-6.73 (m, 1H), 5.16 (d, J =3.8 Hz, 2H), 3.61-3.50 (m, 1H), 3.21 (ddt, J =16.1, 5.7, 1.7 Hz, 1H), 2.99-2.84 (m, 2H), 2.65 (dd, J =16.3, 9.8 Hz, 1H), 2.21 (dddd, J =14.5, 7.3, 4.2, 1.7 Hz, 1H), 1.84 (dddd, J =12.7, 11.1, 10.2, 6.3 Hz, 1H); MS (CIAD ⁺ ) m/z 350 [M+H] ⁺ .

Example 101C: Benzyl [(2R)-6-(benzyloxy)-7-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl]carbamate

[00493] To a solution of the product of Example 101B (2 g, 5.17 mmol) in a mixture of tetrahydrofuran (20 mL) and water (10 mL) was added 1 M aqueous sodium hydroxide (10.35 mL, 10.35 mmol), followed by benzyl chloroformate (1.811 mL, 3 M in toluene, 5.43 mL) dropwise. After 10 min, the reaction mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in boiling ethyl acetate (10 mL), the solution was diluted by the dropwise addition of heptanes (12 mL), and then slowly cooled to room temperature. The solid was collected by filtration, washed with 1:1 ethyl acetate/heptanes (10 mL) and dried in a vacuum oven at 50 °C to give the title compound (1.8513 g, 3.82 mmol, 74% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.47-7.23 (m, 9H), 6.85 (s, 1H), 6.81 (s, 1H), 5.14 (s, 2H), 5.00 (s, 2H), 3.82-3.57 (m, 1H), 2.91 (dd, J = 16.5, 5.3 Hz, 1H), 2.84-2.76 (m, 1H), 2.79-2.66 (m, 1H), 2.47-2.39 (m, 1H), 1.94-1.86 (m, 1H), 1.67-1.55 (m, 1H); MS (CIAD ⁺ ) m/z 484 [M+H] ⁺ .

Example 101D: (R)-tert-butyl 2-((3-(benzyloxy)-7-(((benzyloxy)carbonyl)amino)-1-fluoro-5,6,7,8-tetrahydronaphthalene-2-yl)amino)acetate

[00494] To a suspension of the product of Example 101C (2.0876 g, 4.31 mmol), cesium carbonate (4.21 g, 12.93 mmol), BrettPhos (0.093 g, 0.172 mmol), and the BrettPhos Pd G3 precatalyst (0.078 g, 0.086 mmol) in dioxane (41.8 mL) was added tert -butyl 2-aminoacetate (0.883 mL, 6.47 mmol). The resulting mixture was degassed with 5 additions of vacuum/nitrogen, stirred for 5 min, and then heated to 90°C. After 3 h, the mixture was cooled to below 30 °C, BrettPhos Pd G3 precatalyst (0.078 g, 0.086 mmol) was added, the mixture was degassed with 3 additions of vacuum/nitrogen, stirred for 5 min, and then heated to 90 °C. After 16 h, the mixture was cooled to below 30 °C, BrettPhos Pd G3 precatalyst (0.078 g, 0.086 mmol) was added, and the mixture was degassed with 3 additions of vacuum/nitrogen, stirred for 5 min, and then heated to 90 °C. After 3.5 h, the mixture was cooled to below 30 °C, BrettPhos Pd G3 precatalyst (0.078 g, 0.086 mmol) was added, the mixture was degassed with 3 additions of vacuum/nitrogen, stirring for 5 min, and then heated to 90 °C. After 3 h, the reaction mixture was cooled to ambient temperature and quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (10 mL), and extracted with ethyl acetate (20 mL, 2 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. Silica (10 g) was added to the filtrate, and the resulting mixture was concentrated in vacuo to give a yellow powder. The resulting mixture was loaded dry onto a Teledyne ISCO RediSep Rf ^Gold® 80 g column and eluted with a gradient of 0-35% ethyl acetate in heptanes supplemented with 0.1% triethylamine to give the title compound (1.7647 g, 3.30 mmol, 77% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.50-7.43 (m, 2H), 7.38 (s, 1H), 7.43-7.31 (m, 6H), 7.31 (s, 1H), 6.57 (s, 1H), 5.07 (s, 2H), 5.03 (s, 2H), 4.76 (td, J = 6.8, 2.7 Hz, 1H), 3.88 (dd, J =6.9, 2.6 Hz, 2H), 3.69-3.57 (m, 1H), 2.86 (dd, J =16.4, 5.5 Hz, 1H), 2.75-2.66 (m, 2H), 2.36 (dd, J =16.5, 9.7 Hz, 1H), 1.95-1.87 (m, 1H), 1.60-1.48 (m, 1H), 1.34 (s, 9H); MS (CIAD ⁺ ) m/z 535 [M+H] ⁺ .

[00495] Early fractions yielded the hydrodehalogenation by-product benzyl [(2 R )-6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (0.1848 g, 0.456 mmol, 10.6% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 7.49-7.39 (m, 3H), 7.42-7.34 (m, 6H), 7.37-7.28 (m, 2H), 6.68 (dd, J =11.5, 2.4 Hz, 1H), 6.62 (d, J =2.5 Hz, 1H), 5.06 (s, 2H), 5.03 (s, 2H), 3.69 (s, 1H), 2.90 (dd, J =16.5, 5.6 Hz, 1H), 2.80 (tt, J =16.6, 5.5 Hz, 2H), 2.39 (dd, J =16.6, 9.6 Hz, 1H), 1.93 (dd, J =12.7, 4.1 Hz, 1H), 1.59 (dtd, J = 12.3, 10.5, 5.7 Hz, 1H); MS (APCI ⁺ ) m/z 406 [M+H] ⁺ . Crystals suitable for X-ray crystallography of the hydrodehalogenation by-product were grown by slow evaporation of the methanol solution. X-ray crystallographic analysis confirmed the absolute stereochemistry ( R ).

Example 101E: tert-butyl {[(7R)-3-(benzyloxy)-7-{[(benzyloxy)carbonyl]amino}-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino}acetate

[00496] To a solution of chlorosulfonyl isocyanate (0.430 mL, 4.95 mmol) in dichloromethane (17.6 mL) at 0 °C was added allyl alcohol (0.337 mL, 4.95 mmol). After 30 min, a previously prepared solution of the product of Example 101D (1.7647 g, 3.30 mmol) and N,N -diisopropylamine (1.73 mL, 9.90 mmol) in dichloromethane (17.6 mL) was slowly added along the wall of the flask. After 45 min, the reaction was quenched with water (18 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 9 mL). The organic layers were combined and washed with 1 M aqueous sodium bisulfate (9 mL). The sodium bisulfate layer was extracted with dichloromethane (9 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound, which was used in the next reaction without purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 11.49 (d, J =3.5 Hz, 1H), 7.47-7.24 (m, 10H), 6.73 (s, 1H), 5.69 (ddtd, J =17.4, 10.7, 5.5, 1.5 Hz, 1H), 5.23-5.05 (m, 3H), 5.07-4.95 (m, 6H), 4.59 (dd, J =17.3, 3.0 Hz, 1H), 4.28-4.18 (m, 1H), 4.21-4.07 (m, 2H), 3.74-3.54 (m, 1H), 2.87 (dd, J =16.7, 5.4 Hz, 1H), 2.81-2.68 (m, 1H), 2.38 (dd, J =16.5, 9.6 Hz, 1H), 1.97-1.87 (m, 1H), 1.29 (d, J =3.0 Hz, 9H); MS (CIAD ⁺ ) m/z 642 [M- tert -butyl+H] ⁺ .

Example 101F: benzyl [(2R)-6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate

[00497] To a suspension of the product of Example 101E (2.306 g, 3.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol) in methanol (23 mL) was added a solution of sodium methoxide (5.29 mL, 25 wt % in methanol, 23.13 mmol), and the resulting mixture was heated to 60 °C. After 1.5 h, the reaction mixture was cooled to ambient temperature, quenched with 1 M hydrochloric acid (23 mL), diluted with ethyl acetate (23 mL), and partially concentrated to remove methanol. The crude aqueous mixture was extracted with 2-methyltetrahydrofuran (3 x 23 mL). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered through ^Celite® (5 g) and concentrated in vacuo. The residue was dissolved in acetonitrile (23 mL), ^Celite® (5 g) was added and the mixture was concentrated. The resulting mixture was dry loaded onto a Teledyne ISCO RediSep Rf ^Gold® 40 g column and eluted with a gradient of 0-100% acetonitrile in dichloromethane to give the title compound (1.3459 g, 2.494 mmol, 75% yield). ¹ H NMR (600 MHz, DMSO _-d6 ) δ ppm. 7.51-7.39 (m, 3H), 7.39-7.34 (m, 6H), 7.34-7.28 (m, 2H), 6.82 (s, 1H), 5.12 (s, 2H), 5.08-5.00 (m, 2H), 4.38 (d, J =0.8 Hz, 2H), 3.74-3.70 (m, 1H), 2.95-2.75 (m, 3H), 2.44 (dd, J = 16.6, 9.3 Hz, 1H), 1.97-1.91 (m, 1H), 1.62 (dtd, J = 12.5, 10.4, 5.5 Hz, 1H); MS (CIAD ⁺ ) m/z 540 [M+H] ⁺ .

Example 101G: benzyl [(2R)-6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-1,2,3 ,4-tetrahydronaphthalene-2-yl](2-cyclopentylethyl)carbamate, ammonium salt

[00498] To a solution of the product of Example 101F (0.1 g, 0.185 mmol) in N,N -dimethylformamide (1 mL) was added potassium carbonate (0.026 g, 0.185 mmol) followed by (2-bromoethyl)cyclopentane (0.051 mL, 0.371 mmol). After stirring for 5 min, a suspension of potassium tert-butoxide (0.042 g, 0.371 mmol) in N,N -dimethylformamide (1 mL) was added dropwise over 30 min. After 90 min, additional (2-bromoethyl)cyclopentane (0.30 mL, 0.219 mmol) was added, followed by a suspension of potassium tert -butoxide (0.042 g, 0.371 mmol) in N,N -dimethylformamide (1 mL) over 30 min. After 1 h, the reaction mixture was diluted with water (1 mL) and filtered through a glass microfiber frit. The resulting solution was directly purified by loading onto a Teledyne ISCO 100 g reversed phase C18 column eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by addition of dry ice) to afford the title compound (0.0501 g, 0.036 mmol, 41.4% yield). MS (CIAD ⁺ ) m/z 653 [M+NH ₄ ] ⁺ .

Example 101H: 5-{(7R)-7-[(2-cyclopentylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1 λ ⁶ .2, 5-thiadiazolidine-1,1,3-trione

[00499] To a suspension of the product of Example 101G (0.0300 g, 0.061 mmol) and pentamethylbenzene (0.018 g, 0.123 mmol) in dichloromethane (1.2 mL) at -78 °C was added a solution of boron trichloride (0.368 mL, 0.368 mmol, 1 M in dichloromethane) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The residue was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), and dichloromethane (2 x 2 mL). The crude solid was dissolved in methanol (5 mL), ^Celite® (1 g) was added and the mixture was concentrated. The resulting mixture was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0203 g, 0.049 mmol, 64.3% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.21 (lat s, 1H), 8.47 (lat s, 2H), 6.47 (s, 1H), 3.93 (s, 2H), 3.45-3.38 (m, 1H), 3.09 (dd, J =16.0, 5.4 Hz, 1H), 3.01 (dd, J =10.0, 6.1 Hz, 2H), 2.85-2.65 (m, 2H), 2.57-2.46 (m, 1H), 2.16 (dd, J =11.5, 5.1 Hz, 1H), 1.88-1.42 (m, 9H), 1.18-1.05 (m, 2H); MS (CIAD ⁺ ) m/z 412 [M+H] ⁺ .

Example 102: 5-{(7 R )-7-[(2-cyclobutylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 201)

Example 102A: 2-cyclobutylethyl 4-methylbenzenesulfonate

[00500] To a solution of 2-cyclobutylethanol (0.5 g, 4.99 mmol), 4-dimethylaminopyridine (0.030 g, 0.250 mmol), and p -toluenesulfonyl chloride (1.047 g, 5.49 mmol) in dichloromethane (20 mL) was added N,N -diisopropylethylamine (1.308 mL, 7.49 mmol) at 0 °C. After 30 min, the reaction mixture was warmed to ambient temperature. After 19 h, the reaction was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 2 mL). The organic layers were combined, washed with 1 M aqueous sodium bisulfate (2 mL), dried over anhydrous sodium sulfate, filtered through a pad of silica (1 g), and concentrated in vacuo to give the title compound (0.8254 g, 3.25 mmol, 65% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 7.82-7.74 (m, 2H), 7.39-7.31 (m, 2H), 3.95 (t, J =6.6 Hz, 2H), 2.45 (s, 3H), 2.31 (dt, J =15.7, 7.9 Hz, 1H), 2.11-1.92 (m, 2H), 1.92 -1.73 (m, 2H), 1.72 (k, J =6.7 Hz, 2H), 1.63-1.49 (m, 2H); MS (CIAD ⁺ ) m/z 255 [M+H] ⁺ .

Example 102B: benzyl [(2R)-6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-1,2,3 ,4-tetrahydronaphthalene-2-yl](2-cyclobutylethyl)carbamate, ammonium salt

[00501] To a solution of the product of Example 101F (0.1 g, 0.185 mmol) and the product of Example 102A (0.1615 g, 0.635 mmol) in N,N -dimethylformamide (1 mL) was added a suspension of potassium tert -butoxide (0.104 g, 0.927 mmol) in N,N -dimethylformamide (2 mL) dropwise over 30 minutes. After 1 hour, the reaction mixture was diluted with water (1 mL) and filtered through a glass microfiber frit. The resulting solution was directly purified by loading onto a Teledyne ISCO 50 g reverse phase C18 column eluting with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to afford the title compound as the ammonium salt (0.0577 g, 0.090 mmol, 48.7% yield). MS (APCI ⁾ m/z 639 [M+ _NH4 ] ⁺ .

Example 102C: 5-{(7R)-7-[(2-cyclobutylethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1 λ ⁶ .2, 5-thiadiazolidine-1,1,3-trione

[00502] A suspension of the product of Example 102B (0.0501 g, 0.078 mmol) and 10% palladium hydroxide on carbon (0.05 g, 50 wt % in water, 0.0178 mmol) in tetrahydrofuran (4 mL) was stirred for 19 h under 60 psi of hydrogen. After filtration, Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was dry loaded onto a Teledyne ISCO 50 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0051 g, 0.013 mmol, 16.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.18 (lat s, 1H), 8.26 (lat s, 2H), 6.46 (s, 1H), 3.93 (s, 2H),3.40-3.30 (m, 1H), 3.06 (dd, J =16.0, 5.4 Hz, 1H), 2.88 (dd, J =9.8, 6.2 Hz, 2H), 2.83-2.65 (m, 2H), 2.51-2.46 (m, 1H), 2.32 (hept, J =7.8 Hz, 1H), 2.16-2.00 (m, 3H), 1.92-1.75 (m, 2H), 1.75-1.56 (m, 5H); MS (CIAD ⁺ ) m/z 398 [M+H] ⁺ .

Example 103: 5-[(7 R )-7-{[2-(3,3-difluorocyclobutyl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 202)

Example 103A: 2-(3,3-difluorocyclobutyl)ethyl 4-methylbenzenesulfonate

[00503] To a solution of 2-(3,3-difluorocyclobutyl)ethanol (0.340 g, 2.496 mmol) and triethylamine (0.42 mL, 3.24 mmol) in dichloromethane (12.5 mL) at 0 °C was added 4-methylbenzenesulfonic anhydride (0.978 mL, 3.00 mmol). After 30 min, the reaction mixture was warmed to ambient temperature. After 19 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between diethyl ether (100 mL) and 1 M hydrochloric acid (75 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (75 mL) and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by loading onto a 40 g Teledyne ISCO RediSep Rf ^Gold® column and eluting with a gradient of 0-50% ethyl acetate in heptanes to give the title compound (0.595 g, 2.049 mmol, 82% yield). ¹ H NMR (400 MHz, _CDCl3 ) δ ppm 7.83-7.75 (m, 2H), 7.39-7.33 (m, 2H), 4.01 (t, J = 6.1 Hz, 2H), 2.69-2.54 (m, 2H), 2.46 (s, 3H), 2.24-2.05 (m, 3H), 1.88-1.80 (m, 2H).

Example 103B: benzyl [(2R)-6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl][2-(3,3-difluorocyclobutyl)ethyl]carbamate

[00504] To a solution of the product of Example 101F (0.1 g, 0.185 mmol) and the product of Example 103A (0.140 g, 0.482 mmol) in N,N -dimethylformamide (1 mL) was added a suspension of potassium tert -butoxide (0.104 g, 0.927 mmol) in N,N -dimethylformamide (2 mL) dropwise over 30 minutes. After 1 hour, the reaction mixture was diluted with water (1 mL) and filtered through a glass microfiber frit. The filtrate was purified directly by loading onto a Teledyne ISCO 50 g reverse phase C18 column eluting with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to afford the title compound as the ammonium salt (0.0488 g, 0.072 mmol, 39% yield). MS (APCI ⁾ m/z 676 [M+ _NH4 ] ⁺ .

Example 103C: 5-[(7R)-7-{[2-(3,3-difluorocyclobutyl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl] -1 λ ^6,2,5 -thiadiazolidine-1,1,3-trione

[00505] A suspension of the product of Example 103B (0.0488 g, 0.072 mmol) and 10% palladium hydroxide on carbon (0.05 g, 50 wt % in water, 0.0178 mmol) in tetrahydrofuran (4 mL) was stirred for 20 h under 60 psi of hydrogen. After filtration, ^Celite® (1 g) was added and the mixture was concentrated in vacuo. The resulting mixture was dry loaded onto a Teledyne ISCO 50 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0093 g, 0.021 mmol, 29.7% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 9.15 (s, 1H), 8.17 (s, 2H), 6.46 (s, 1H), 3.93 (s, 2H), 3.46-3.33 (m, 1H), 3.05 (dd, J =15.9, 5.3 Hz, 1H), 2.92 (t, J =7.8 Hz, 2H), 2.86-2.62 (m, 4H), 2.52-2.43 (m, 1H), 2.36-2.07 (m, 4H), 1.78 (k, J = 7.6 Hz, 2H), 1.64 (cd, J = 11.4, 7.8 Hz, 1H); MS (CIAD ⁺ ) m/z 434 [M+H] ⁺ .

Example 104: 5-{(7 R )-1-fluoro-3-hydroxy-7-[(3-methylpentyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 203)

Example 104A: 3-methylpentyl 4-methylbenzenesulfonate

[00506] To a solution of 3-methylpentan-1-ol (0.534 mL, 4.3 mmol), 4-dimethylaminopyridine (0.053 g, 0.430 mmol), and N,N -diisopropylethylamine (2.253 g, 1.667 mmol) in dichloromethane (10 mL) was added p-toluenesulfonyl chloride (0.902, 4.73 mmol) at 0 °C. After 30 min, the reaction mixture was warmed to ambient temperature. After 19 h, the reaction was quenched with water (5 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 2 mL). The organic layers were combined, washed with 1 M aqueous sodium bisulfate (2 mL), dried over anhydrous sodium sulfate, filtered through a pad of silica (1 g), and concentrated in vacuo to give the title compound (0.8135 g, 3.17 mmol, 73.8% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm. 7.82-7.77 (m, 2H), 7.39-7.32 (m, 2H), 4.11-4.01 (m, 2H), 2.45 (d, J = 0.7 Hz, 3H), 1.72-1.63 (m, 1H), 1.48-1.37 (m, 2H), 1.32-1.22 (m, 1H), 1.16-1.06 (m, 1H), 0.86-0.77 (m, 6H); MS (APCI ⁺ ) m/z 257 [M+H] ⁺ .

Example 104B: benzyl [(2R)-6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl](3-methylpentyl)carbamate

[00507] To a solution of the product of Example 101F (0.1 g, 0.185 mmol) and the product of Example 104A (0.143 g, 0.556 mmol) in N,N -dimethylformamide (1 mL) was added a suspension of potassium tert -butoxide (0.104 g, 0.927 mmol) in N,N -dimethylformamide (2 mL) dropwise over 30 minutes. After 1 hour, the reaction mixture was diluted with water (1 mL) and filtered through a glass microfiber frit. The resulting solution was directly purified by loading onto a Teledyne ISCO 50 g reverse phase C18 column eluting with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to afford the title compound as the ammonium salt (0.0723 g, 0.113 mmol, 60.9% yield). MS (APCI ⁾ m/z 641 [M+ _NH4 ] ⁺ .

Example 104C: 5-{(7R)-1-fluoro-3-hydroxy-7-[(3-methylpentyl)amino]-5,6,7,8-tetrahydronaphthalene-2-yl}-1 λ ⁶ .2, 5-thiadiazolidine-1,1,3-trione

[00508] To a suspension of the product of Example 104B (0.0723 g, 0.113 mmol) and pentamethylbenzene (0.033 g, 0.226 mmol) in dichloromethane (3.6 mL) at -78 °C was added a solution of boron trichloride (1.128 mL, 1 M in dichloromethane, 1.128 mmol) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The mixture was warmed to ambient temperature and concentrated in vacuo. The residue was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), and dichloromethane (2 x 2 mL). The crude solid was dissolved in methanol (5 mL) and ^Celite® (1 g) was added. The mixture was concentrated. The resulting mixture was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0146 g, 0.037 mmol, 32.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.19 (br s, 1H), 8.39 (br s, 2H), 6.47 (s, 1H), 3.94 (s, 2H), 3.47-3.37 (m, 1H), 3.18-2.93 (m, 3H), 2.86-2.66 (m, 2H), 2.57-2.46 (m, 1H), 2.20-2.12 (m, 1H), 1.74-1.56 (m, 2H), 1.52-1.27 (m, 3H), 1.26-1.10 (m, 1H), 0.92-0.83 (m, 6H); MS (APCI ⁺ ) m/z 400 [M+H] ⁺ .

Example 105: 5-{(7 R )-7-[(3-ethylpentyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 204)

Example 105A: 3-ethylpentyl 4-methylbenzenesulfonate

[00509] To a solution of 3-ethylpentan-1-ol (0.5 mL, 4.3 mmol), 4-dimethylaminopyridine (0.053 g, 0.430 mmol), and N,N -diisopropylethylamine (2.253 g, 1.667 mmol) in dichloromethane (10 mL) was added p-toluenesulfonyl chloride (0.902, 4.73 mmol) at 0 °C. After 30 min, the reaction mixture was warmed to ambient temperature. After 19 h, the reaction was quenched with water (5 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 2 mL). The organic layers were combined, washed with 1 M aqueous sodium bisulfate (2 mL), dried over anhydrous sodium sulfate, filtered through a pad of silica (1 g), and concentrated in vacuo to give the title compound (0.9158 g, 3.39 mmol, 79% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 7.82-7.77 (m, 2H), 7.37-7.32 (m, 2H), 4.05 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 1.61-1.56 (m, 2H), 1.36-1.12 (m, 5H), 0.78 (t, J = 7.3 Hz, 6H); MS (CIAD ⁺ ) m/z 271 [M+H] ⁺ .

Example 105B: benzyl [(2R)-6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl](3-ethylpentyl)carbamate

[00510] To a solution of the product of Example 101F (0.1 g, 0.185 mmol) and the product of Example 105A (0.150 g, 0.556 mmol) in N,N -dimethylformamide (1 mL) was added a suspension of potassium tert -butoxide (0.104 g, 0.927 mmol) in N,N -dimethylformamide (2 mL) dropwise over 30 minutes. After 1 hour, the reaction mixture was diluted with water (1 mL) and filtered through a glass microfiber frit. The resulting solution was directly purified by loading onto a 50 g Teledyne ISCO reversed phase C18 column eluting with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound as the ammonium salt (0.0305 g, 0.047 mmol, 25.1% yield). MS (APCI ⁺ ) m/z 655 [M+NH ₄ ] ⁺ .

Example 105C: 5-{(7R)-7-[(3-ethylpentyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl}-1 λ ⁶ .2, 5-thiadiazolidine-1,1,3-trione

[00511] To a suspension of the product of Example 105B (0.0305 g, 0.047 mmol) and pentamethylbenzene (0.014 g, 0.093 mmol) in dichloromethane (3.6 mL) at -78 °C was added a solution of boron trichloride (0.466 mL, 1 M in dichloromethane, 0.466 mmol) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) followed by ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The residue was triturated with heptanes (3 x 2 mL), 1:1 ethyl acetate/heptanes (2 x 2 mL), and dichloromethane (2 x 2 mL). The crude solid was dissolved in methanol (5 mL). ^Celite® (1 g) was added to the mixture and the resulting mixture was concentrated. The residue was dry loaded onto a Teledyne ISCO 50 g reversed phase C18 column eluting with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0156 g, 0.038 mmol, 81% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.23 (br s, 1H), 8.49 (br s, 2H), 6.47 (d, J = 1.4 Hz, 1H), 3.96-3.91 (m, 2H), 3.51-3.37 (m, 1H), 3.10 (dd, J = 16.0, 5.4 Hz, 1H), 3.05-2.97 (m, 2H), 2.86-2.66 (m, 2H), 2.59-2.51 (m, 1H), 2.21-2.13 (m, 1H), 1.69 (cd, J = 11.4, 5.6 Hz, 1H), 1.60-1.54 (m, 2H), 1.35-1.26 (m, 5H), 0.85 (t, J =7.0 Hz, 6H); MS (CIAD ⁺ ) m/z 414 [M+H] ⁺ .

Example 106: 8-fluoro-6-hydroxy- N -(3-methylbutyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 205)

Example 106A: 4-nitrophenyl isopentyl carbamate

[00512] A solution of 3-methylbutan-1-amine (105 mg, 1.2 mmol) in dichloromethane (1 mL) was added dropwise to a stirred solution of 4-nitrophenyl chloroformate (242 mg, 1.200 mmol) and triethylamine (182 mg, 1.800 mmol) in dichloromethane (3 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and maintained at room temperature for 18 h. The reaction mixture was then diluted with ethyl acetate (60 mL), washed with 0.2 N aqueous HCl (15 mL) and brine (2×15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40 g), eluting with heptane/ethyl acetate (0 to 20%) to give the title compound (205 mg, 0.813 mmol, 68% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.26 (dd, J = 8.2 Hz, 2H), 8.02 (m, 1H), 7.39 (dd, J = 8.2 Hz, 2H), 3.11 (dt, J = 8.7 Hz, 2H), 1.62 (m, 1H), 1.38 (m, 2H), 0.89 (d, J = 7 Hz, 6H).

Example 106B: 6-(benzyloxy)-8-fluoro-N-(3-methylbutyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00513] A mixture of the product of Example 65A (122 mg, 0.18 mmol), the product of Example 106A (59.0 mg, 0.234 mmol), and potassium carbonate (87 mg, 0.630 mmol) in N,N -dimethylformamide (0.8 mL) was stirred at 60 °C for 1 hour. The mixture was cooled to room temperature, 0.5 N aqueous HCl (1.6 mL) and N,N -dimethylformamide (1 mL) were added. The solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm, 25×150 mm column, flow rate 80 mL/min, gradient 10-75% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (76 mg, 0.146 mmol, yield 81%). MS (ESI ^- ) m/z 503 [MH] ^- .

Example 106C: 8-fluoro-6-hydroxy-N-(3-methylbutyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00514] To a mixture of 1,2,3,4,5-pentamethylbenzene (57.1 mg, 0.385 mmol) and Example 106B (67 mg, 0.128 mmol) in dichloromethane (3 mL) at -78 °C was added trichloroborane (1.927 mL, 1.93 mmol, 1 M in dichloromethane). The mixture was stirred at -78 °C for 20 min, then at 0 °C for 30 min. The mixture was quenched with ethanol (2 mL) and concentrated under reduced pressure. The residue was washed with heptane (3 x 2 mL) and dichloromethane (2 x 2 mL) and dried under reduced pressure. The resulting residue was dissolved in methanol/ N,N -dimethylformamide (1:1, 3 mL) and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm, 25×150 mm, 80 mL/min flow rate, 5-55% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (36 mg, 0.083 mmol, 65% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 9.23 (br. s, 1H), , 6.57 (t, J=5.4 Hz, 1H), 6.49 (s, 1H), 4.35 (s, 2H), 3.94 (s, 2H), 3.49 (t, J=5.8 Hz, 2H), 3.05 (m, 2H), 2.64 (t, J=5.8 Hz, 2H), 1.56 (m, 1H), 1.31 (m, 2H), 0.86 (d, J=6.6 Hz, 6H); MS (IER ^- ) m/z 413 [MH] ^- .

Example 107: 8-fluoro-6-hydroxy- N -(2-methylpropyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 206)

[00515] The title compound was prepared using the methodologies described in Example 106, replacing 3-methylbutan-1-amine with 2-methylpropan-1-amine. ¹ H NMR (600 MHz, DMSO _-d6 ) δ ppm 10.22 (br s, 1H), 6.67 (m, 1H), 6.56 (br s, 1H), 4.38 (s, 2H), 4.35 (s, 2H), 2 .86 (m, 2H), 2.67 (t, J=6 Hz, 2H), 1.70 (m, 1H), 0.88 (m, 2H), 0.81 (d, J=7 Hz, 6H); MS (IER ^- ) m/z 399 [MH] ^- .

Example 108: 5-{8-fluoro-6-hydroxy-2-[3-(pyridin-3-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 207)

[00516] The title compound was prepared using the methodologies described in Example 71, substituting 3-(3-bromopropyl)pyridine for 4-bromo-2-methylbutan-2-ol. ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm 10.31 (lat s, 2H), 8.77 (lat s, 1H), 8.71 (d, J = 7 Hz, 1H), 8.36 (d, J = 8 Hz, 1H), 7.88 (dd, J = 8, 7 Hz, 1H), 6.59 (s, 1H), 4.41 (lat s, 2H), 4.16 (s, 2H), 3.23 (m, 4H), 2.98-3.08 (m, 2H), 2.83 (m, 2H), 2.13 (m, 2H); MS (IER ^- ) m/z 419 [MH] ^- .

Example 109: 5-{2-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 208)

Example 109A: 5-{6-(benzyloxy)-2-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00517] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.10 mmol, Example 93A) were added acetonitrile (0.34 mL), 4-(chloromethyl)-3,5-dimethylisoxazole (0.022 g, 0.15 mmol), and potassium carbonate (0.070 g, 0.51 mmol). The vial was then heated to 50 °C. After 90 min, the reaction mixture was cooled to ambient temperature and filtered through diatomaceous earth with dichloromethane/methanol (9:1 v/v). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography [4 g column, 0-20% gradient of methanol in dichloromethane] to give the title compound (0.041 g, 0.082 mmol, 80% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 7.53-7.45 (m, 2H), 7.38-7.31 (m, 2H), 7.31-7.26 (m, 1H), 6.72 (s, 1H), 5.10 (s, 2H), 3.94 (s, 2H), 3.45 (s, 2H), 3.43 (s, 2H), 2.73 (t, J =5.8 Hz, 2H), 2.57 (t, J =5.8 Hz, 2H), 2.35 (s, 3H), 2.17 (s, 3H); MS (CIAD ⁺ ) m/z 501.3 [M+H] ⁺ .

Example 109B: 5-{2-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00518] A vial containing a suspension of 5-{6-(benzyloxy)-2-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.076 g, 0.15 mmol, Example 109A) and 1,2,3,4,5-pentamethylbenzene (0.068 g, 0.46 mmol) in dichloromethane (1.5 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane, 1.2 mL, 1.2 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 10 min, the mixture was recooled to -78 °C, diluted with dichloromethane (5 mL) and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and the residue was co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [60 g Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to afford the title compound as the corresponding ammonium salt (0.048 g, 0.11 mmol, 74% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 9.28 (br s, 1H), 7.27-6.85 (m, 3H), 6.48 (s, 1H), 3.93 (s, 2H), 3.55 (br s, 4H), 2.85-2.68 (br s, 4H), 2.38 (s, 3H), 2.20 (s, 3H); MS (APCI ⁺ ) m/z 411.3 [M+H] ⁺ .

Example 110: 5-{8-fluoro-6-hydroxy-2-[2-(1,3,5-trimethyl-1H - pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 209)

Example 110A: 5-(6-(benzyloxy)-8-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline -7-yl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide

[00519] To a vial containing the product of Example 93A (theoretical 0.10 mmol) were added 1,2-dichloroethane (0.31 mL) and triethylamine (0.028 mL, 0.20 mmol). The mixture was stirred for 5 minutes. A solution of 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetaldehyde (0.023 g, 0.15 mmol, Example 110C) in 1,2-dichloroethane (0.20 mL) was then added and the resulting suspension was stirred at ambient temperature. After 10 minutes, sodium triacetoxyhydroborate (0.054 g, 0.26 mmol) was added. After 12 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate (20 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [4 g column, 0-25% gradient of methanol in dichloromethane] to give the title compound (0.049 g, 0.093 mmol, 91% yield). MS (APCI ⁾ m/z 528.4 [M+H] ⁺ .

Example 110B: 5-{8-fluoro-6-hydroxy-2-[2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00520] A vial containing a suspension of 5-(6-(benzyloxy)-8-fluoro-2-(2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.049 g, 0.093 mmol, Example 110A) and 1,2,3,4,5-pentamethylbenzene (0.041 g, 0.28 mmol) in dichloromethane (0.93 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (0.74 mL, 0.74 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 10 min, the mixture was recooled to -78 °C, diluted with dichloromethane (5 mL) and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [60 g Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.027 g, 0.062 mmol, 67% yield). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 6.59 (s, 1H), 4.27 (br s, 2H), 4.02 (s, 2H), 3.55 (s, 3H), 3.43 (br s, 2H), 3.13 (dd, J = 8.9, 6.2 Hz, 2H), 3.05-2.94 (m, 2H), 2.74 (dd, J = 10.6, 6.4 Hz, 2H), 2.12 (s, 3H), 2.05 (s, 3H); MS (APCI ⁺ ) m/z 438.3 [M+H] ⁺ .

Example 110C: 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetaldehyde

[00521] 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (0.050 g, 0.32 mmol) and dichloromethane (1.6 mL) were added to the flask. The white suspension was stirred at ambient temperature and Dess-Martin periodinane (0.206 g, 0.486 mmol) was added portionwise. After 2 h, the solids were removed by filtration through diatomaceous earth with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was treated with tert -butyl methyl ether (20 mL) and filtered through diatomaceous earth. The filtrate was stirred with 0.1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1 v/v) (20 mL) for 15 min. The layers were then separated and the aqueous phase was extracted with tert -butyl ether (2×15 mL). The organic phases were combined, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [4 g column, gradient acetonitrile in dichloromethane 0-50%] to give the title compound (0.032 g, 0.21 mmol, 65% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 9.48 (t, J = 2.1 Hz, 1H), 3.62 (s, 3H), 3.44 (d, J = 2.1 Hz, 2H), 2.09 (s, 3H), 1.98 (s, 3H).

Example 111: 5-{8-fluoro-6-hydroxy-2-[2-(pyrimidin-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 210)

Example 111A: 2-(pyrimidin-5-yl)ethyl 4-methylbenzenesulfonate

[00522] 4-Dimethylaminopyridine (4.9 mg, 0.040 mmol, 5.0 mol %) was added to a solution of p -toluenesulfonyl chloride (161.0 mg, 0.846 mmol, 1.1 equivalents), 2-(pyrimidin-5-yl)ethanol (100.0 mg, 0.806 mmol, 1 equivalent), and triethylamine (0.34 mL, 2.42 mmol, 3.0 equivalents) in dichloromethane (4.0 mL) at 23 °C. The reaction mixture was stirred for 19 h at 23 °C. The reaction mixture was then diluted sequentially with ethyl acetate (25 mL), saturated aqueous sodium bicarbonate (3 mL), and water (3 mL). The resulting biphasic mixture was transferred to a separatory funnel and the resulting layers were separated. The organic layer was washed with saturated aqueous sodium chloride solution (5 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was dissolved in 2% ethyl acetate-ether (v/v, 2 mL) and diluted with pentane (5 mL). A white precipitate formed. The suspension was filtered through a pad of diatomaceous earth (0.5 cm × 1.0 cm). The filter cake was washed with ether (3 × 3 mL). The filtrates were combined and the combined filtrates were concentrated. The resulting title compound was used without further purification in the next step.

Example 111B: 5-{6-(benzyloxy)-8-fluoro-2-[2-(pyrimidin-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00523] A suspension of the product of Example 111A (80.0 mg, 0.29 mmol, 1.4 equivalents), 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominal 0.203 mmol, 1 equivalent, Example 54A), and potassium carbonate (80.0 mg, 0.58 mmol, 2.9 equivalents) in acetonitrile (0.8 mL) was placed in a heating block preheated to 70 °C. The reaction mixture was stirred for 18 hours at 70 °C. The reaction mixture was cooled to 23 °C. The cooled reaction mixture was diluted with dimethyl sulfoxide (1 mL) and water (0.5 mL). The diluted mixture was purified by reverse-phase flash column chromatography (50 g ^RediSep® Gold C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol for 3 column volumes, flow rate = 60 mL/min) to give the title compound (52 mg, 52% yield, two steps). MS (APCI ⁺ ) m / z 498 [M+H] ⁺ .

Example 111C: 5-{8-fluoro-6-hydroxy-2-[2-(pyrimidin-5-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00524] A solution of boron trichloride in dichloromethane (1.0 M, 0.65 mL, 0.65 mmol, 6.2 equivalents) was added to a suspension of the product of Example 111B (52 mg, 0.105 mmol, 1 equivalent) in dichloromethane (0.53 mL) at -78 °C. The reaction vessel was immediately transferred to a cooling bath at 0 °C. The reaction mixture was stirred for 15 min at 0 °C. The reaction vessel was then transferred to a cooling bath at -78 °C. Additional boron trichloride in dichloromethane (1.0 M, 1.00 mL, 1.00 mmol, 9.5 equivalents) was added at -78 °C. The reaction vessel was immediately removed from the cooling bath and heated to 23 °C for 1.5 h. The reaction vessel was transferred to a cooling bath at -78 °C and cooled over 30 min to -78 °C. The reaction mixture was slowly diluted with ethanol (2.5 mL) at -78 °C. The diluted mixture was heated over 15 min to 23 °C. The heated mixture was concentrated. The resulting residue was triturated successively with 1% methanol-dichloromethane (v/v, 1.0 mL), ethyl acetate (2.0 mL), 30% acetone-heptanes (2.0 mL), and heptanes (2.0 mL) to give the title compound (36 mg, 0.088 mmol, 84% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 11.28 (br, 1H), 9.11 (s, 1H), 8.81 (s, 2H), 6.70 (s, 1H), 4.58-4.19 (m, 5H), 3.60-3.48 (m, 2H), 3.39-3.24 (m, 4H), 3.10-2.96 (m, 1H); MS (APCI ⁺ ) m / z 408 [M+H] ⁺ .

Example 112: 5-{2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 211)

Example 112A: 5-{6-(benzyloxy)-2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00525] To a vial containing the product of Example 93A (theoretical 0.203 mmol) were added 1,2-dichloroethane (0.61 mL) and triethylamine (0.057 mL, 0.41 mmol). The mixture was stirred for 5 minutes. A solution of 2-(3,5-dimethylisoxazol-4-yl)acetaldehyde (0.042 g, 0.31 mmol, Example 112C) in 1,2-dichloroethane (0.41 mL) was then added and the resulting suspension was stirred at ambient temperature. After 10 minutes, sodium triacetoxyhydroborate (0.108 g, 0.508 mmol) was added. After 12 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate (20 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 minutes. The layers were then separated and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [12 g column, gradient of methanol in dichloromethane 0-25%] to give the title compound (0.088 g, 0.17 mmol, 84% yield). MS ( ^APCI ) m/z 515.3 [M+H] ⁺ .

Example 112B: 5-{2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00526] A vial containing a suspension of 5-{6-(benzyloxy)-2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.085 g, 0.17 mmol) and 1,2,3,4,5-pentamethylbenzene (0.073 g, 0.50 mmol) in dichloromethane (1.7 mL) was cooled to -78 °C with stirring under nitrogen atmosphere. Trichloroborane (1.0 M in dichloromethane) (1.3 mL, 1.3 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 10 min, the mixture was recooled to -78 °C, diluted with dichloromethane (5 mL) and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [100 g Isco Redi Sep Rf ^Gold® C18 column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.039 g, 0.092 mmol, 56% yield). ¹ H NMR (600 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 6.59 (s, 1H), 4.16 (br s, 2H), 3.97 (s, 2H), 3.40-3.17 (br m, 4H), 3.05-2.92 (m, 2H), 2.78 (t, J =8.3 Hz, 2H), 2.33 (s, 3H), 2.19 (s, 3H); MS (ESI ⁺ ) m/z 424.9 [M+H] ⁺ .

Example 112C: 2-(3,5-dimethylisoxazol-4-yl)acetaldehyde

[00527] 2-(3,5-Dimethylisoxazol-4-yl)ethanol (0.200 g, 1.42 mmol) and dichloromethane (7.1 mL) were added to the flask. The white suspension was stirred at room temperature and Dess-Martin periodinane (0.721 g, 1.70 mmol) was added portionwise. After 2 h, the solids were removed by filtration through diatomaceous earth with tert-butyl methyl ether. The filtrate was concentrated under reduced pressure. The residue was treated with tert -butyl methyl ether (50 mL) and filtered through diatomaceous earth. The filtrate was stirred with 0.1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1 v/v) (50 mL) for 15 min. The layers were then separated and the aqueous phase was extracted with tert -butyl ether (2 x 50 mL). The organic phases were combined, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.061 g, 0.44 mmol, 31% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 9.66 (t, J = 1.8 Hz, 1H), 3.41 (d, J = 1.7 Hz, 2H), 2.33 (s, 3H), 2.18 (s, 3H).

Example 113: 5-{2-[(3,5-dimethyl-1H- pyrazol -4-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 212)

Example 113A: 5-{6-(benzyloxy)-2-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00528] To a vial containing the product of Example 93A (theoretical 0.15 mmol) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The resulting mixture was stirred for 5 min, then 3,5-dimethyl- 1H- pyrazole-4-carbaldehyde (0.028 g, 0.23 mmol, Example 113C) was added. After 10 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 13 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (20 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [100 g Isco Redi Sep Rf ^Gold® C18 column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.045 g, 0.090 mmol, 59% yield). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.44 (d, J = 7.3 Hz, 2H), 7.37-7.30 (m, 2H), 7.30-7.23 (m, 1H), 6.85 (s, 1H), 5.12 (s, 2H), 4.22 (br s, 4H), 4.00 (s, 2H), 3.34 (br s, 2H), 3.02 (br s, 2H), 2.20 (s, 6H); MS (APCI ⁺ ) m/z 500.4 [M+H] ⁺ .

Example 113B: 5-{2-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00529] A vial containing a suspension of 5-{6-(benzyloxy)-2-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.044 g, 0.088 mmol, Example 113A) and 1,2,3,4,5-pentamethylbenzene (0.039 g, 0.26 mmol) in dichloromethane (0.88 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (0.71 mL, 0.71 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 10 min, the mixture was recooled to -78 °C, diluted with dichloromethane (5 mL) and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.023 g, 0.056 mmol, 64% yield). ¹ H NMR (600 MHz, DMSO -d ₆ -D ₂ O) δ ppm 6.55 (s, 1H), 4.05 (br s, 4H), 3.97 (s, 2H), 3.24 (br s, 2H), 2.92 (br s, 2H), 2.18 (s, 6H); MS (CIAD ⁺ ) m/z 410.3 [M+H] ⁺ .

Example 113C: 3,5-dimethyl-1H-pyrazole-4-carbaldehyde

[00530] (3,5-Dimethyl-1H-pyrazol-4-yl)methanol (0.188 g, 1.49 mmol) and dichloromethane (7.5 mL) were added to the flask. The white suspension was stirred at room temperature and Dess-Martin periodinane (0.948 g, 2.24 mmol) was added portionwise. After 2 h, the solids were removed by filtration through diatomaceous earth with tert-butyl methyl ether. The filtrate was concentrated under reduced pressure. The residue was treated with tert -butyl methyl ether (50 mL) and filtered through diatomaceous earth. The filtrate was stirred with 0.1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1 v/v) (50 mL) for 15 min. The layers were then separated and the aqueous phase was extracted with tert -butyl ether (2 x 50 mL). The organic phases were combined, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.085 g, 0.69 mmol, 46% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.97 (s, 1H), 2.52 (s, 6H).

Example 114: 5-{8-fluoro-6-hydroxy-2-[(1,3,5-trimethyl-1H - pyrazol-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 213)

Example 114A: 5-{6-(benzyloxy)-8-fluoro-2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00531] To a vial containing the product of Example 93A (0.15 mmol theoretical) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 1,3,5-trimethyl- 1H- pyrazole-4-carbaldehyde (0.032 g, 0.23 mmol) was added. After 10 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 13 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (20 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [100 g Isco Redi Sep Rf ^Gold® C18 column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.050 g, 0.097 mmol, 64% yield). ¹ H NMR (600 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.48-7.42 (m, 2H), 7.36-7.30 (m, 2H), 7.30-7.24 (m, 1H), 6.84 (s, 1H), 5.12 (s, 2H), 4.17 (br s, 4H), 3.99 (s, 2H), 3.63 (s, 3H), 3.27 (br s, 2H), 2.98 (br s, 2H), 2.22 (s, 3H), 2.14 (s, 3H); MS (APCI ⁺ ) m/z 514.4 [M+H] ⁺ .

Example 114B: 5-{8-fluoro-6-hydroxy-2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00532] A vial containing a suspension of 5-{6-(benzyloxy)-8-fluoro-2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.047 g, 0.092 mmol, Example 114A) and 1,2,3,4,5-pentamethylbenzene (0.041 g, 0.28 mmol) in dichloromethane (0.92 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (0.73 mL, 0.73 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 10 min, the mixture was recooled to -78 °C, diluted with dichloromethane (5 mL) and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.028 g, 0.066 mmol, 72% yield). ¹ H NMR (600 MHz, pyridine -d ₅ ) δ ppm. 6.77 (s, 1H), 4.66 (s, 2H), 3.78 (s, 2H), 3.67 (s, 2H), 3.63 (s, 3H), 2.83 (s, 4H), 2.39 (s, 3H), 2.15 (s, 3H); MS (APCI ⁺ ) m/z 424.2 [M+H] ⁺ .

Example 114C: 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde

[00533] (1,3,5-Trimethyl-1H-pyrazol-4-yl)methanol (0.209 g, 1.49 mmol) and dichloromethane (7.5 mL) were added to the flask. The white suspension was stirred at ambient temperature and Dess-Martin periodinane (0.759 g, 1.79 mmol) was added portionwise. After 2 h, the solids were removed by filtration through diatomaceous earth with tert-butyl methyl ether. The filtrate was concentrated under reduced pressure. The residue was treated with tert -butyl methyl ether (50 mL) and filtered through diatomaceous earth. The filtrate was stirred with 0.1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1 v/v) (50 mL) for 15 min. The layers were then separated and the aqueous phase was extracted with tert -butyl ether (2 x 50 mL). The organic phases were combined, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.101 g, 0.731 mmol, 49% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 9.89 (s, 1H), 3.73 (s, 3H), 2.50 (s, 3H), 2.42 (s, 3H).

Example 115: 5-{8-fluoro-6-hydroxy-2-[2-(oxan-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 214)

Example 115A: 5-{6-(benzyloxy)-8-fluoro-2-[2-(oxan-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00534] To a vial containing the product of Example 93A (theoretical 0.15 mmol) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.029 g, 0.23 mmol) was added. After 10 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 14 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (20 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound. This material was used without further purification. MS (APCI ⁺ ) m/z 504.3 [M+H] ⁺ .

Example 115B: 5-{8-fluoro-6-hydroxy-2-[2-(oxan-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00535] A vial containing a suspension of 5-{6-(benzyloxy)-8-fluoro-2-[2-(oxan-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (theoretical 0.15 mmol) and 1,2,3,4,5-pentamethylbenzene (0.068 g, 0.46 mmol) in dichloromethane (1.5 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.2 mL, 1.2 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 15 min and then the dry ice-acetone bath was replaced with an ice water bath. After 15 min, the mixture was recooled to -78 °C, diluted with dichloromethane (5 mL) and quenched by successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g Biotage ^® Sfär C18 Duo 100 column 30 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.026 g, 0.064 mmol, 42% yield). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 6.58 (s, 1H), 4.18 (s, 2H), 3.99 (s, 2H), 3.79 (dd, J =11.1, 3.4 Hz, 2H), 3.40-3.30 (m, 2H), 3.25 (td, J =11.7, 1.9 Hz, 2H), 3.21-3.13 (m, 2H), 2.97 (t, J =6.2 Hz, 2H), 1.69-1.60 (m, 2H), 1.60-1.47 (m, 3H), 1.25-1.09 (m, 2H); MS (CIAD ⁺ ) m/z 414.3 [M+H] ⁺ .

Example 116: 5-[2-(2-cyclohexyl-2-hydroxyethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 215)

Example 116A: 5-[6-(benzyloxy)-2-(2-cyclohexyl-2-hydroxyethyl)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00536] A suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominally 0.19 mmol, 1 equivalent, Example 54A), sodium perchlorate (96 mg, 0.78 mmol, 4.0 equivalents), and 2-cyclohexyloxirane (50 mg, 0.39 mmol, 2.0 equivalents) in acetonitrile (0.5 mL) was stirred for 66 h at 23 °C. Additional sodium perchlorate (114 mg, 0.93 mmol, 4.8 equivalents) was added at 23 °C. The reaction mixture was stirred for 5 h at 23 °C. The mixture was then diluted with water (0.5 mL) and dimethyl sulfoxide (1.0 mL). The diluted mixture was purified by reverse-phase flash column chromatography (100 g RediSep ^Gold® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 80 mL/min) to give the title compound (37 mg, 0.069 mmol, 37% yield). MS ( ^APCI ) m / z 518 [M+H] ⁺ .

[00537] Example 116B: 5-[2-(2-cyclohexyl-2-hydroxyethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00538] A solution of boron trichloride in dichloromethane (1.0 M, 1.07 mL, 1.07 mmol, 15.0 equivalents) was added to a suspension of the product of Example 116A (52 mg, 0.071 mmol, 1 equivalent) in dichloromethane (0.7 mL) at -78 °C. The reaction vessel was immediately transferred to a cooling bath at 0 °C. The reaction mixture was stirred for 40 min at 0 °C. The reaction vessel was then transferred to a cooling bath at -78 °C and cooled over 10 min to -78 °C. The reaction mixture was slowly diluted with ethyl acetate (1.0 mL) and ethanol (1.0 mL) at -78 °C. The diluted mixture was warmed to 23 °C over 15 min. The heated mixture was concentrated. The resulting residue was triturated with 20% acetone and heptanes (3×2.0 mL) to give the title compound (9.0 mg, 0.021 mmol, 30% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.73 (s, 1H), 4.52 (s, 2H), 4.21-4.08 (m, 2H), 3.64-3.45 (m, 3H), 2.96 (dt, J ⁼ 10.9, 5.6 Hz, 2H), 1.80-0.89 (m, 13H); MS (APCI) m / z 428 [M+H] ⁺ .

Example 117: 5-[8-fluoro-6-hydroxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 216)

Example 117A: 5-[6-(benzyloxy)-8-fluoro-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00539] To a vial containing a suspension of the product of Example 65A (150 mg, 0.297 mmol) in acetonitrile (1.5 mL) was added potassium carbonate (205 mg, 1.484 mmol) and the mixture was stirred at ambient temperature for 10 minutes. 1-Bromo-2-methoxyethane (0.028 mL, 0.298 mmol) was then added and the mixture was heated to 50 °C for 40 hours. The solution was cooled to room temperature and then filtered through diatomaceous earth, eluting sequentially with acetonitrile and methanol. The filtrate was concentrated under reduced pressure. The residue was filtered through a glass microfiber frit and washed with a minimal amount of methanol. The resulting solution was purified by reversed-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/min, gradient of acetonitrile 5-100% in 0.025 M aqueous ammonium bicarbonate buffer, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound (93 mg, 0.207 mmol, yield 69.7%). MS (APCI ⁺ ) m/z 450 [M+H] ⁺ .

Example 117B: 5-[8-fluoro-6-hydroxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00540] Trichloroborane (1.0 M in dichloromethane, 1068 μL, 1.068 mmol) was added dropwise to a vial containing a suspension of the product of Example 117A (60 mg, 0.133 mmol) and 1,2,3,4,5-pentamethylbenzene (59.4 mg, 0.400 mmol) in dichloromethane (0.929 mL) cooled to -78 °C. The resulting mixture was stirred at -78 °C for 15 min, then at 0 °C for 45 min, and then at ambient temperature for 1.5 h. The mixture was again cooled to -78 °C, diluted with dichloromethane (5 mL), and quenched by adding ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then warmed to ambient temperature and stirred for an additional 15 min. The mixture was diluted with ethanol and concentrated under reduced pressure. The residue was filtered through a glass microfiber frit and washed with a minimum amount of methanol. The resulting solution was purified by reversed-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30 x 100 mm, flow rate 40 mL/min, gradient of acetonitrile 5-100% in 0.025 M aqueous ammonium bicarbonate buffer, pH adjusted to 10 with ammonium hydroxide)] to give the ammonium salt of the title compound (24.1 mg, 0.067 mmol, yield 50.2%). ¹ H NMR (600 MHz, DMSO -d ₆ /D ₂ O) δ ppm. 7.36 (s, 3H), 6.61 (d, J =4.8 Hz, 1H), 4.24 (s, 2H), 3.99 (s, 2H), 3.76 (t, J =5.0 Hz, 2H), 3.38 (s, 4H), 3.33 (s, 3H), 3.02 (s, 2H); MS (CIAD ⁺ ) m/z 360.33 [M+H] ⁺ .

Example 118: 5-[8-fluoro-6-hydroxy-2-(3-methoxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 217)

Example 118A: 5-[6-(benzyloxy)-8-fluoro-2-(3-methoxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ6,2,5 ^- thiadiazolidin-1 ,1,3-trione

[00541] To a vial containing a suspension of the product of Example 65A (100 mg, 0.198 mmol) in acetonitrile (1.5 mL) were added potassium carbonate (137 mg, 0.989 mmol) and 1-bromo-3-methoxypropane (0.033 mL, 0.297 mmol). The mixture was stirred at 60 °C for 4 hours. The solution was filtered through a pad of diatomaceous earth with excess acetonitrile and concentrated under reduced pressure. The residue was then filtered through a glass microfiber frit rinsed with a minimal amount of methanol. The resulting solution was purified by reversed-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/min, gradient of 5-100% acetonitrile in 0.025 M aqueous ammonium bicarbonate buffer, pH adjusted to 10 with ammonium hydroxide] to afford the title compound (40.4 mg, 0.087 mmol, yield 44.1%). MS (APCI ⁺ ) m/z 464 [M+H] ⁺ .

Example 118B: 5-[8-fluoro-6-hydroxy-2-(3-methoxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1 λ 6,2,5-thiadiazolidine-1,1,3-trione

[00542] Trichloroborane (1.0 M in dichloromethane, 604 μL, 0.604 mmol) was added dropwise to a vial containing a suspension of the product of Example 118A (35 mg, 0.076 mmol) and 1,2,3,4,5-pentamethylbenzene (33.6 mg, 0.227 mmol) in dichloromethane (755 μL) cooled to -78 °C. The resulting mixture was stirred at -78 °C for 15 min and then at 0 °C for 15 min. The mixture was again cooled to -78 °C, diluted with dichloromethane (5 mL), and quenched with ethyl acetate (3 mL) and ethanol (3 mL). The mixture was warmed to ambient temperature and stirred for 15 min. The mixture was diluted with ethanol and concentrated under reduced pressure. The residue was filtered through a glass microfiber frit washed with a minimum amount of methanol. The resulting filtrate was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30 x 100 mm, flow rate 40 mL/min, 5-100% acetonitrile gradient in 0.025 M aqueous ammonium bicarbonate buffer, pH adjusted to 10 with ammonium hydroxide)] to afford the title compound as the ammonium salt (23.7 mg, 0.058 mmol, 77% yield). ¹ H NMR (500 MHz, DMSO -d ₆ /D ₂ O) δ ppm. 7.31 (s, 6H), 6.59 (s, 1H), 4.13 (s, 4H), 3.98 (s, 2H), 3.41 (t, J =5.9 Hz, 2H), 3.23 (s, 3H), 2.98 (s, 2H), 1.97 (s, 2H); MS (CIAD ⁺ ) m/z 374 [M+H] ⁺ .

Example 119: 5-[2-(3-aminopropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 218)

Example 119A: tert-Butyl {3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]propyl}carbamate, ammonium salt

[00543] Triethylamine (0.12 mL, 0.86 mmol, 3.4 equivalents) was added to a suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominally 0.25 mmol, 1 equivalent, Example 54A) in acetonitrile (0.80 mL) at 23 °C. The reaction mixture was stirred for 30 min at 23 °C. A solution of tert -butyl (3-oxopropyl)carbamate (57 mg, 0.33 mmol, 1.3 equivalents) in acetonitrile (0.3 mL) was added at 23 °C. The reaction mixture was stirred for 3 min at 23°C. Sodium triacetoxyborohydride (135 mg, 0.64 mmol, 2.5 equivalents) was added in one portion at 23°C. The reaction mixture was stirred for 1.5 h at 23°C. The reaction mixture was successively diluted with aqueous sodium bisulfate solution (1.0 mL, CAUTION: gas evolution) and dimethyl sulfoxide (1.0 mL). The diluted mixture was purified by reverse phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (70 mg, 0.12 mmol, 50% yield, two steps). MS (APCI ⁺ ) m/z 549 [M+H] ⁺ .

Example 119B: 5-[2-(3-aminopropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, bis(hydrochloride) salt

[00544] To a suspension of the product of Example 119A (78 mg, 0.142 mmol, 1 equivalent) in dichloromethane (1.4 mL) was added a solution of boron trichloride in dichloromethane (1.0 M, 2.06 mL, 2.06 mmol, 14.5 equivalents). The reaction vessel was immediately transferred to a cooling bath at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. The reaction vessel was then transferred to a cooling bath at -78 °C and cooled to -78 °C over 15 min. Additional boron trichloride in dichloromethane (1.0 M, 1.00 mL, 1.00 mmol, 9.5 equivalents) was added at -78 °C. The reaction vessel was immediately removed from the cooling bath and heated to 23 °C for 1.5 h. The reaction vessel was transferred to a cooling bath at -78 °C and cooled to -78 °C for 15 min. The reaction mixture was slowly diluted with ethyl acetate (1.0 mL) and ethanol (1.0 mL) at -78 °C. The diluted mixture was heated to 23 °C for 15 min. The heated mixture was concentrated. The resulting residue was triturated successively with ethanol (3 x 1.0 mL), acetonitrile (1.0 mL), and ethyl acetate (1.0 mL) to give the title compound (55 mg, 0.13 mmol, 90% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 10.89 (br, 1H), 10.13 (br, 1H), 6.63 (s, 1H), 4.46-4.36 (m, 1H), 4.17-4.08 (m, 3H), 3.71-3.58 (m, 2H), 3.32-3.13 (m, 4H), 2.99-2.86 (m, 2H), 2.19-2.07 (m, 2H); MS (APCI ⁺ ) m/z 359 [M+H] ⁺ .

Example 120: 5-{8-fluoro-6-hydroxy-2-[3-(piperidin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 219)

Example 120A: tert-Butyl 4-{3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]propyl}piperidine-1-carboxylate

[00545] Triethylamine (0.100 mL, 0.718 mmol) was added to a suspension of the product of Example 65A (182 mg, 0.359 mmol) in dichloromethane (1 mL) and the resulting mixture was stirred at ambient temperature for 5 min. Tert -butyl 4-(3-oxopropyl)piperidine-1-carboxylate (130 mg, 0.539 mmol) in dichloromethane (1 mL) was then added and the resulting mixture was allowed to stir for an additional 10 min. Sodium triacetoxyhydroborate (190 mg, 0.898 mmol) was then added and the reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was then diluted with dichloromethane and stirred with saturated sodium bicarbonate (20 mL) for 20 min. The mixture was extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, flow rate 50 mL/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with _CO2 (s)]) to give the title compound (73.4 mg, 0.119 mmol, yield 33.1%). MS ( ^APCI ) m/z 618 [M+H] ⁺ .

Example 120B: 5-{8-fluoro-6-hydroxy-2-[3-(piperidin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00546] Trichloroborane (1.0 M in dichloromethane, 778 μL, 0.778 mmol) was added dropwise to a vial containing a suspension of the product of Example 120A (60 mg, 0.097 mmol) and 1,2,3,4,5-pentamethylbenzene (43.3 mg, 0.292 mmol) in dichloromethane (973 μL) cooled to -78 °C. The resulting mixture was stirred at -78 °C for 15 min and then at 0 °C for 15 min. The mixture was again cooled to -78 °C, diluted with dichloromethane (5 mL), and quenched with ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then warmed to ambient temperature and stirred for 15 min. The mixture was diluted with ethanol and concentrated under reduced pressure. The residue was filtered through a glass microfiber frit washed with a minimum amount of methanol. The filtrate was purified by reversed-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30 x 100 mm, flow rate 40 mL/min, gradient of 5-100% acetonitrile in 0.025 M aqueous ammonium bicarbonate buffer, pH adjusted to 10 with ammonium hydroxide] to give the title compound (10.5 mg, 0.025 mmol, yield 25.3%). ¹ H NMR (400 MHz, DMSO -d ₆ /D ₂ O) δ ppm. 6.56 (s, 1H), 3.99 (s, 2H), 3.28-3.20 (m, 2H), 3.16 (s, 3H), 2.92 (s, 3H), 2.82 (td, J =12.8, 3.0 Hz, 2H), 1.87-1.76 (m, 3H), 1.67 (s, 2H), 1.54 (s, 1H), 1.32-1.17 (m, 5H); MS (CIAD ⁺ ) m/z 427 [M+H] ⁺ .

Example 121: 5-[8-fluoro-6-hydroxy-2-(3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 220)

Example 121A: 5-[6-(benzyloxy)-8-fluoro-2-(3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00547] Triethylamine (0.11 mL, 0.79 mmol, 3.1 equivalents) and isovaleraldehyde (0.04 mL, 0.37 mmol, 1.5 equivalents) were added sequentially to a suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominally 0.254 mmol, 1 equivalent, Example 54A) in acetonitrile (0.6 mL) at 23 °C. The reaction mixture was stirred for 5 min at 23 °C. Significant dissolution of the suspended reactants was observed within 1 min after the addition of isovaleraldehyde. Sodium triacetoxyborohydride (75 mg, 0.36 mmol, 1.4 equivalents) was added in one portion at 23°C. The reaction mixture was stirred for 1 h at 23°C. The reaction mixture was diluted with saturated aqueous ammonium chloride (0.5 mL) and dimethyl sulfoxide (3.0 mL). The diluted mixture was purified by reverse-phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (82 mg, 0.17 mmol, 70% yield, two steps); MS (APCI) m/z 462 [M+H] ⁺ .

Example 121B: 5-[8-fluoro-6-hydroxy-2-(3-methylbutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, hydrochloride salt

[00548] To a suspension of the product of Example 121A (82 mg, 0.178 mmol, 1 equivalent) in dichloromethane (1.0 mL) at -78 °C was added a solution of boron trichloride in dichloromethane (1.0 M, 1.80 mL, 1.80 mmol, 10.1 equivalents). The reaction vessel was immediately transferred to a cooling bath at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C. The reaction vessel was then transferred to a cooling bath at -78 °C and cooled over 15 minutes to -78 °C. The reaction mixture was slowly diluted with ethanol (1.0 mL) at -78 °C. The diluted mixture was warmed over 15 minutes to 23 °C. The heated mixture was concentrated. The resulting residue was triturated successively with ethanol (3×1.0 mL), acetonitrile (1.0 mL), and ethyl acetate (1.0 mL) to give the title compound (8.0 mg, 0.016 mmol, 11% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.33 (lat, 1H), 9.84 (lat, 1H), 6.61 (s, 1H), 4.46 (d, J =15.2 Hz, 1H), 4.20 (s, 2H), 4.13 (dd, J =15.5, 7.8 Hz, 1H), 3.31-2.93 (m, 6H), 1.71-1.56 (m, 3H), 0.92 (d, J =5.5 Hz); MS (CIAD ⁺ ) m/z 372 [M+H] ⁺ .

Example 122: tert -butyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate (Compound 221)

[00549] To a 20 mL Barnstead Hast C reactor containing 5% palladium on carbon (0.140 g, 0.613 mmol) were added tert-butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate (0.075 g, 0.15 mmol, Example 44H) and tetrahydrofuran (4 mL). The resulting mixture was stirred at 50 °C for 25 h under a hydrogen atmosphere of 64 psi. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and purified by reverse phase chromatography [column 120 g Biotage ^® Sfär C18 Duo 100 30 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to afford the title compound as the corresponding ammonium salt along with some impurities. This mixture was re-purified by reverse phase chromatography [30 g ^Biotage® Sfär C18 Duo 100 column 30 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound as the corresponding ammonium salt (0.023 g, 0.055 mmol, 36% yield). ¹ H NMR (600 MHz, DMSO -d ₆ -D ₂ O) δ ppm 6.51 (s, 1H), 4.34 (s, 2H), 3.97 (s, 2H), 3.49 (t, J = 5.8 Hz, 2H), 2.66 (t, J = 5.9 Hz, 2H), 1.39 (s, 9H); MS (ESI ^- ) m/z 400.1 [MH] ^- .

Example 123: 5-{8-fluoro-6-hydroxy-2-[(7-oxabicyclo[2.2.1]heptan-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 222)

Example 123A: 5-{6-(benzyloxy)-8-fluoro-2-[(7-oxabicyclo[2.2.1]heptan-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00550] Triethylamine (0.21 mL, 1.50 mmol, 3.0 equivalents) and 7-oxabicyclo[2.2.1]heptane-2-carbaldehyde (82 mg, 0.65 mmol, 1.3 equivalents) were added sequentially to a suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominally 0.5 mmol, 1 equivalent, Example 54A) in acetonitrile (1.0 mL) at 23 °C. The reaction mixture was stirred for 5 min at 23 °C. Sodium triacetoxyborohydride (138 mg, 0.65 mmol, 1.3 equivalents) was added in one portion at 23°C. The reaction mixture was stirred for 18 h at 23°C. The reaction mixture was diluted with saturated aqueous ammonium chloride (0.6 mL) and dimethyl sulfoxide (3.0 mL). The diluted mixture was purified by reverse phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (224 mg, 0.432 mmol, 89% yield, two steps). MS (APCI ⁺ ) m/z 502 [M+H] ⁺ .

Example 123B: 5-{8-fluoro-6-hydroxy-2-[(7-oxabicyclo[2.2.1]heptan-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00551] A suspension of palladium on carbon (10 wt %, 42 mg, 0.04 mmol, 10.0 mol %), ammonium formate (126 mg, 1.99 mmol, 5.0 equivalents), and the product of Example 123A (200 mg, 0.399 mmol, 1 equivalent) in ethanol (2.0 mL) was stirred for 3 h at 23 °C. The reaction mixture was filtered through a pad of diatomaceous earth (1.0 cm x 0.5 cm). The filter cake was washed with methanol (3 x 1.0 mL). The filtrates were combined and concentrated. The resulting residue was purified by reverse phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column, eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (130 mg, 0.30 mmol, 76% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.66 (br, 1H), 6.56 (s, 1H), 4.61-4.39 (m, 2H), 4.03 (s, 2H), 3.11-2.77 (m, 2H), 2.45-2.21 (m, 1H), 1.80-1.66 (m, 1H), 1.62-1.25 (m, 5H); MS (APCI ⁺ ) m/z 412 [M+H] ⁺ .

Example 124: 5-{7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 223)

Example 124A: 5-{3-(benzyloxy)-7-[(3,3-difluoropropyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00552] To a suspension of the product of Example 67F (0.5294 g, 1.309 mmol) and 3,3-difluoropropan-1-amine hydrochloride (0.254 g, 1.931 mmol) in ethanol (10 mL) was added triethylamine (0.550 mL, 3.93 mmol). After 30 min, sodium cyanoborohydride (0.099 g, 1.571 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.150 mL, 7.85 mmol) and the resulting mixture was diluted with acetonitrile (10 mL) and water (2 mL). ^Celite® (4 g) was added and the mixture was concentrated in vacuo to give a white powder. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.3947 g, 0.816 mmol, 62.4% yield). MS ( ^APCI ) m/z 484 [M+H] ⁺ .

Example 124B: 5-{7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00553] To a suspension of 5-{3-(benzyloxy)-7-[(3,3-difluoropropyl)amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.3947 g, 0.816 mmol) and pentamethylbenzene (0.225 g, 1.518 mmol) in dichloromethane (8 mL) and 1,2-dichloroethane (4 mL) at -78°C was added a solution of boron trichloride (9.10 mL, 1 M in dichloromethane, 9.10 mmol) slowly down the side of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched successively with ethyl acetate (4 mL) and ethanol (4 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 5 mL), 1:1 ethyl acetate/heptane (2 x 5 mL), and dichloromethane (2 x 5 mL) to give a residue that was dissolved in methanol (20 mL). ^Celite® (3 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.1798 g, 0.457 mmol, 60.2% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 9.26 (s, 1H), 8.41 (s, 2H), 6.47 (s, 1H), 6.23 (tm, J =56.0, 4.3 Hz, 1H), 3.94 (s, 2H), 3.43 (br s, 1H), 3.17 (t, J =7.8 Hz, 2H), 3.07 (dd, J =16.0, 5.5 Hz, 1H), 2.85-2.68 (m, 2H), 2.56-2.50 (m, 1H), 2.30-2.16 (m, 2H), 2.16-2.10 (m, 1H), 1.69 (cd, J = 11.2, 5.5 Hz, 1H); MS (CIAD ⁺ ) m/z 394 [M+H] ⁺ .

Example 125: 5-(8-fluoro-6-hydroxy-2-{1-[(1,3,5-trimethyl-1H - pyrazol-4-yl)methyl]azetidin-3-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 224)

Example 125A: tert-butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]azetidine-1-carboxylate, ammonium salt

[00554] To a vial containing the product of Example 93A (theoretical 0.407 mmol) were added 1,2-dichloroethane (2.0 mL) and triethylamine (0.11 mL, 0.81 mmol). The mixture was stirred for 10 min, then tert-butyl 3-oxoazetidine-1-carboxylate (0.105 g, 0.611 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.216 g, 1.02 mmol) was added. After 12 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 spherical column 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound as the corresponding ammonium salt (0.207 g, 0.367 mmol, 90% yield). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.49-7.43 (m, 2H), 7.36-7.31 (m, 2H), 7.31-7.25 (m, 1H), 6.76 (s, 1H), 5.09 (s, 2H), 3.98 (s, 2H), 3.95 (s, 2H), 3.81 (s, 2H), 3.54 (s, 2H), 3.45 (s, 1H), 2.80 (d, J = 6.0 Hz, 2H), 2.68 (s, 2H), 1.35 (s, 9H); MS (APCI ⁺ ) m/z 588.3 [M+CH ₃ CN+H] ⁺ .

Example 125B: 5-[2-(azetidin-3-yl)-6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt

[00555] A vial containing a suspension of tert -butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2( 1H )-yl]azetidine-1-carboxylate, ammonium salt (0.180 g, 0.319 mmol) in dichloromethane (1.1 mL) was cooled to 0 °C. 2,2,2-Trifluoroacetic acid (0.25 mL, 3.2 mmol) was then added dropwise, after which the cooling bath was removed. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (2×1 mL) and then co-evaporated with methanol (1 mL) to give the title compound. This material was used without further purification. MS (APCI ⁺ ) m/z 447.3 [M+H] ⁺ .

Example 125C: 5-[6-(benzyloxy)-8-fluoro-2-{1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]azetidin-3-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00556] To a vial containing 5-[2-(azetidin-3-yl)-6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.319 mmol) were added 1,2-dichloroethane (1.6 mL) and triethylamine (0.089 mL, 0.64 mmol). The mixture was stirred for 10 min, then 1,3,5-trimethyl-1 H -pyrazole-4-carbaldehyde (0.066 g, 0.48 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.169 g, 0.798 mmol) was added. After 37 hours, additional 1,3,5-trimethyl-1 H -pyrazole-4-carbaldehyde (0.066 g, 0.48 mmol) was added, followed after 15 minutes by additional sodium triacetoxyhydroborate (0.169 g, 0.798 mmol). After 42 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 minutes. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.057 g, 0.10 mmol, 32% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.58 (br s, 1H), 7.53-7.44 (m, 2H), 7.37-7.31 (m, 2H), 7.31-7.22 (m, 1H), 6.75 (s, 1H), 5.11 (s, 2H), 4.17 (2 overlapping singlets, 3H), 4.04 (br s, 2H), 3.98 (s, 2H), 3.81 (br s, 1H), 3.64 (s, 3H), 3.47 (s, 2H), 3.40 (br s, 1H), 2.78 (t, J = 5.8 Hz, 2H), 2.59 (t, J = 5.8 Hz, 2H), 2.26 (s, 3H), 2.16 (s, 3H); MS (CIAD ⁺ ) m/z 569.4 [M+H] ⁺ .

Example 125D: 5-(8-fluoro-6-hydroxy-2-{1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]azetidin-3-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00557] To a 20 mL Barnstead Hast C reactor containing 5% palladium on carbon (0.80 g, 3.5 mmol) were added 5-[6-(benzyloxy)-8-fluoro-2-{1-[(1,3,5-trimethyl- 1H- pyrazol-4-yl)methyl]azetidin-3-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.070 g, 0.12 mmol) and tetrahydrofuran (4 mL). The resulting mixture was stirred at 25 °C for 42 h under a hydrogen atmosphere of 45 psi. The catalyst was then removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure and purified by reverse phase chromatography [60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate solution, pH adjusted to 7 with dry ice)] to give the title compound (0.011 g, 0.024 mmol, 19% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.21 (s, 1H), 6.47 (s, 1H), 4.11 (s, 2H), 4.07-3.98 (m, 2H), 3.94 (s, 2H), 3.82 (br s, 2H), 3.64 (s, 3H), 3.41 (s, 3H), 2.73 (t, J =5.4 Hz, 2H), 2.56 (t, J =5.4 Hz, 2H), 2.25 (s, 3H), 2.15 (s, 3H); MS (CIAD ⁺ ) m/z 479.3 [M+H] ⁺ .

Example 126: 5-{8-fluoro-6-hydroxy-2-[2-(7-oxabicyclo[2.2.1]heptan-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 225)

Example 126A: 2-(7-oxabicyclo[2.2.1]heptan-2-yl)acetaldehyde

[00558] To a suspension of (methoxymethyl)triphenylphosphonium chloride (326 mg, 0.95 mmol, 1.0 equivalent) in tetrahydrofuran (5 mL) was added a solution of potassium tert -butoxide in tetrahydrofuran (1.0 M, 1.0 mL, 1.0 mmol, 1.1 equivalent) at 0 °C. The reaction mixture was stirred for 5 min at 0 °C. A solution of 7-oxabicyclo[2.2.1]heptane-2-carbaldehyde (120 mg, 0.95 mmol, 1 equivalent) in tetrahydrofuran (1.0 mL) was added at 0 °C. The reaction mixture was stirred for 5 min at 0 °C. Thin layer chromatography analysis showed consumption of starting material (new zone: Rf=0.60, 3:1 heptanes:ethyl acetate, developed with 2,4-dinitrophenylhydrazine). Aqueous hydrochloric acid (1.0 M, 4.0 mL, 4.0 mmol, 4.2 equivalents) was added at 0 °C. The reaction mixture was immediately removed from the cooling bath and the reaction mixture was stirred for 20 h at 23 °C. Then the reaction mixture was diluted successively with ether (15 mL) and pentane (10 mL). The diluted mixture was stirred for 10 min. Then the resulting biphasic mixture was transferred to a separatory funnel and the resulting layers were separated. The organic layer was washed successively with saturated aqueous sodium bicarbonate (5 mL) and saturated aqueous sodium chloride (5 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The filter cake was washed with 50% ether-pentane (v/v, 5.0 mL). The supernatant was filtered through a silica plug (1.5 cm × 0.5 cm). The filter cake was washed with 50% ether-pentane (v/v, 3 × 1 mL). The filtrates were combined and concentrated. The resulting residue was used without further purification (R _f = 0.18, 3:1 heptane:ethyl acetate, developed with 2,4-dinitrophenylhydrazine).

Example 126B: 5-{6-(benzyloxy)-8-fluoro-2-[2-(7-oxabicyclo[2.2.1]heptan-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00559] Sodium triacetoxyborohydride (97 mg, 0.46 mmol, 1.2 equivalents) was added in one portion to a suspension of the product of Example 126A (nominally 0.95 mmol, 2.5 equivalents), triethylamine (0.16 mL, 1.14 mmol, 3.0 equivalents), and 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominally 0.38 mmol, 1 equivalent, Example 54A) in acetonitrile (1.5 mL) at 23 °C. The reaction mixture was stirred for 5 hours at 23 °C. The reaction mixture was then diluted with saturated aqueous ammonium chloride (0.5 mL) and dimethyl sulfoxide (1.0 mL). The diluted mixture was purified by reverse-phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (80 mg, 0.15 mmol, 41% yield). MS ( ^APCI ) m/z 516 [M+H] ⁺ .

Example 126C: 5-{8-fluoro-6-hydroxy-2-[2-(7-oxabicyclo[2.2.1]heptan-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00560] A suspension of palladium on carbon (10 wt %, 16 mg, 0.016 mmol, 10.0 mol %), ammonium formate (49 mg, 0.78 mmol, 5.0 equivalents), and the product of Example 126B (80 mg, 0.155 mmol, 1 equivalent) in ethanol (1.5 mL) was stirred for 2 h at 23 °C. The reaction mixture was filtered through a pad of diatomaceous earth (1.0 cm x 0.5 cm). The filter cake was washed with methanol (3 x 1.0 mL). The filtrates were combined and concentrated. The resulting residue was purified by reverse phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column, eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (42 mg, 0.095 mmol, 61% yield). 1H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.70 (lat, 1H), 9.59 (lat, 1H), 6.57 (s, 1H), 4.50 (t, J =5.0 Hz, 1H), 4.44 (t, J =5.3 Hz, 0.5H)*, 4.38 (t, J =4.8 Hz, 0.5H)*, 4.26 (d, 4.6 Hz, 0.5H)*, 4.13 (lat, 0.5H)*, 3.94 (s, 2H), 3.67 (lat, 0.5H), 3.24-3.08 (m, 1H), 2.98 (lat, 2H), 1.96-1.36 (m, 8H), 1.26-1.19 (m, 0.5H)*, 0.96 (dd, J = 11.4, 4.61 Hz, 0.5H)*. * denotes isomeric resonances. MS (APCI ^- ) m/z 424 [MH] ^- .

Example 127: 5-(2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1H - pyrazol-4-yl]ethyl}-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 226)

Example 127A: ethyl 3-acetyl-4-oxopentanoate

[00561] Pentene-2,4-dione (10 g, 100 mmol) was added dropwise to a mixture of NaH (4.19 g, 105 mmol) in tetrahydrofuran (240 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C under N ₂ . A solution of ethyl 2-bromoacetate (16.68 g, 100 mmol) in tetrahydrofuran (60 mL) was added dropwise to the mixture at 20 °C, and the mixture was stirred for 18 h under N ₂ . The mixture was quenched with saturated NH ₄ Cl (200 mL), and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated to give the title compound (~20 g), which was used in the next step without further purification. MS (ESI ⁺ ) m/z 187 [M+H] ⁺ .

Example 127B: ethyl 2-(3,5-dimethyl-1H-pyrazol-4-yl)acetate

[00562] To a solution of the product of Example 127A (10.5 g) in methanol (100 mL) was added hydrazine hydrate (2.96 g, 59.2 mmol) at 20 °C. The mixture was stirred for 3 h at 20 °C. The mixture was concentrated under reduced pressure. The crude mixture was then diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (7.091 g, 38.9 mmol, 74% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 1.05-1.35 (m, 5 H) 1.96-2.27 (m, 6 H) 3.25-3.48 (m, 2 H) 3.95-4.24 (m, 2 H).

Example 127C: ethyl 2-(1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate

[00563] To a solution of the product of Example 127B (2.55 g, 14.0 mmol) in tetrahydrofuran (20 mL) was added potassium 2-methylpropan-2-olate (2.120 g, 18.89 mmol) at 20 °C and the mixture was stirred for 10 min. Then, 2,2-difluoroethyl trifluoromethanesulfonate (8.09 g, 37.8 mmol) was added to the mixture at 0 °C. The mixture was stirred for 12 h at 20 °C. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (3.2 g, 13.0 mmol, 93% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm 2.14 (s, 3 H) 2.42 (t, J= 7.32 Hz, 2 H) 2.50 (br s, 5 H) 3.28-3.41 (m, 5 H) 4.39 (td, J= 14.95, 3.75 Hz, 2 H) 4.55-4.70 (m, 1 H) 6.08-6.44 (m, 1 H).

Example 127D: 2-(1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl)ethanol

[00564] To a solution of the product of Example 127C (2.8 g, 11.4 mmol) in tetrahydrofuran (30 mL) was added LiAlH ₄ (0.665 g, 17.51 mmol) in portions at 0 °C under N ₂ . The mixture was stirred for 1 h at 0 °C under N ₂ . To the mixture were added water (0.7 mL), aqueous NaOH (0.7 mL, 15% in water), and water (2.1 mL) sequentially at 0 °C. After 10 min, the mixture was filtered and concentrated under reduced pressure to give the title compound (1.8 g, 8.8 mmol, 77% yield), which was used in the next step without purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.14 (s, 3 H) 2.42 (t, J= 7.32 Hz, 2 H) 2.50 (lat s, 5 H) 3.28-3.41 (m, 5 H) 4.39 (td, J= 14.95, 3.75 Hz, 2 H) 4.55-4.70 (m, 1 H) 6.08-6.44 (m, 1 H).

Example 127E: 2-(1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetaldehyde

[00565] To a solution of the product of Example 127D (100 mg, 0.441 mmol) in dichloromethane (2 mL) was added Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1 H )-one) (280 mg, 0.661 mmol) at 20 °C. The mixture was stirred for 1 h at 20 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate) to give the title compound (20 mg, 0.099 mmol, 20% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.11-2.29 (m, 6 H) 3.33-3.46 (m, 2 H) 4.30-4.42 (m, 2 H) 5.88-6.25 (m, 1 H) 9.59 (t, J = 2.25 Hz, 1 H).

Example 127F: methyl 2-(N-(3-((benzylamino)methyl)-6-(benzyloxy)-4-bromo-2-fluorophenyl)-2,2,2-trifluoroacetamido)acetate

[00566] To a solution of phenylmethanamine (16.16 g, 151 mmol) in dichloromethane (350 mL) was added dropwise a solution of the product of Example 44A (55 g, 101 mmol) in dichloromethane (600 mL) at 0 °C. The mixture was stirred for 30 min at 20 °C. To the mixture were added acetic acid (0.288 mL, 5.03 mmol) and sodium triacetoxyborohydride (32.0 g, 151 mmol) sequentially at 20 °C. The resulting mixture was stirred for 12 h at 20 °C. One additional 55 g vial was set up as described above. The mixtures were combined and diluted with water (800 mL), extracted with ethyl acetate (3 x 500 mL). _The organic phases were combined, dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (100 g, 171 mmol, yield 77%). ¹ H NMR (400 MHz, _CDCl3 ) δ ppm 3.67 (s, 3 H) 3.71-3.82 (m, 2 H) 3.87-4.06 (m, 3 H) 4.61 (d, J= 16.88 Hz, 1 H) 4.89-5.21 (m, 2 H) 7.10 (s, 1 H) 7.30-7.52 (m, 10 H).

Example 127G: methyl {[6-(benzyloxy)-3-{[benzyl(prop-2-en-1-yl)amino]methyl}-4-bromo-2-fluorophenyl](trifluoroacetyl)amino}acetate

[00567] To a solution of the product of Example 127F (47.5 g, 73.3 mmol) in N,N -dimethylformamide (500 mL) were added 3-bromoprop-1-ene (13.30 g, 110 mmol) and K ₂ CO ₃ (30.4 g, 220 mmol) at 20 °C. The mixture was stirred for 12 h at 40 °C. Two additional reactions, weighing 5 g and 47.5 g, respectively, were carried out as described above. The reaction mixtures were combined, diluted with brine (1000 mL), and extracted with ethyl acetate (3 x 1000 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (97 g, 0.156 mol, yield 91%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.08 (d, J= 6.48 Hz, 2 H) 3.51-3.62 (m, 1 H) 3.59 (d, J= 2.08 Hz, 1 H) 3.65 (s, 3 H) 3.68-3.82 (m, 2 H) 3.97 (d, J= 16.75 Hz, 1 H) 4.56 (d, J= 16.75 Hz, 1 H) 4.97-5.28 (m, 4 H) 5.94 (ddt, J= 17.04, 10.35, 6.48, 6.48 Hz, 1 H) 7.08 (d, J= 1.71 Hz, 1 H) 7.27 (m, 11 H).

Example 127H: methyl {[2-benzyl-6-(benzyloxy)-8-fluoro-4-methylidene-1,2,3,4-tetrahydroisoquinolin-7-yl](trifluoroacetyl)amino}acetate

[00568] To a solution of the product of Example 127G (30 g, 46.3 mmol) in toluene (300 mL) were added chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (SPhos Pd G2, 3.34 g, 4.63 mmol) and Cs ₂ CO ₃ (45.2 g, 139 mmol) at 20 °C. The mixture was heated at 100 °C for 4 days. Two additional reactions at a weight of 30 g were carried out as described above. The reaction mixtures were combined, filtered, and diluted with water (1000 mL). The mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl _acetate =10:1) to give the title compound (44 g, 81.1 mmol, yield 52.8%). ¹ H NMR (400 MHz, _CDCl3 ) δ ppm 3.26-3.45 (m, 2 H) 3.62-3.82 (m, 7 H) 3.99 (d, J = 16.88 Hz, 1 H) 4.65 (d, J= 16.76 Hz, 1 H) 5.01-5.19 (m, 3 H) 5.59 (s, 1 H) 7.09 (d, J= 1.00 Hz, 1 H) 7.28-7.46 (m, 10 H).

Example 127I: methyl {[6-(benzyloxy)-8-fluoro-4-methylidene-1,2,3,4-tetrahydroisoquinolin-7-yl](trifluoroacetyl)amino}acetate

[00569] To a solution of the product of Example 127H (10.5 g, 17.42 mmol) and 1,8-bis(dimethylamino)naphthalene (3.73 g, 17.42 mmol) in 1,2-dichloroethane (200 mL) was added 1-chloroethyl chloroformate (3.74 g, 26.1 mmol) dropwise at 0 °C. The mixture was stirred for 1 h at 20 °C. The solvent was removed under reduced pressure. The residue was diluted with methanol (200 mL). The mixture was stirred for 1 h at 55 °C. One additional reaction at 2 g and three addition reactions at 10.5 g were carried out as described above. The reaction mixtures were combined and concentrated under reduced pressure to give the crude title compound (78 g), which was used in the next step without further purification. MS (ESI ⁺ ) m/z 453 [M+H] ⁺ .

Example 127J: tert-butyl 6-(benzyloxy)-8-fluoro-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-methylidene-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00570] To a solution of the product of Example 127I (35 g, 69.6 mmol) in tetrahydrofuran (350 mL) and water (70 mL) were added sodium bicarbonate (11.70 g, 139 mL) and di- tert- butyl dicarbonate (19.40, 84 mmol) sequentially at 0 °C. The mixture was stirred for 1 h at 20 °C. Two additional reactions at 8 g and 35 g were carried out as described above. The reaction mixtures were combined, diluted with water (1500 mL), and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (38 g, 68.8 mmol, yield 89%). ¹ H NMR (400 MHz, _CDCl3 ) δ ppm 1.49 (s, 8H), 3.59-3.74 (m, 3H), 3.92-4.06 (m, 1H), 4.10-4.31 (m, 2H), 4.49-4.74 (m, 3H), 5.04-5.18 (m, 2H), 5.26 (br s, 1H), 5.46-5.61 (m, 1H), 7.04 (s, 1H), 7.33-7.48 (m, 6H).

Example 127K: tert-butyl 6-(benzyloxy)-8-fluoro-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00571] To a solution of the product of Example 127J (10 g, 16.29 mmol) in water (20 mL) and tetrahydrofuran (100 mL) were added sequentially osmium tetroxide (0.511 mL, 0.4 mmol/L in tertiary butanol) and sodium periodate (10.45 g, 48.9 mmol) at 20 °C. The mixture was stirred for 1 h at 20 °C. One additional reaction of 2 g and three addition reactions of 10.5 g were carried out as described above. The reaction mixtures were combined, quenched with saturated Na ₂ S ₂ O ₃ (200 mL), and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (14.5 g, 26.2 mmol, yield 37.4%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.29-1.44 (m, 9H), 3.63 (s, 3H), 4.30-4.44 (m, 2H), 4.47-4.66 (m, 2H), 4.74 (br d, J= 15.51 Hz, 2H), 5.24-5.45 (m, 2H), 7.42 (br d, J= 2.75 Hz, 4H), 7.54 (s, 1H).

Example 127L: tert-butyl 6-(benzyloxy)-4,4,8-trifluoro-7-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00572] To a solution of the product of Example 127K (3 g, 4.87 mmol) in dichloromethane (30 mL) was added diethylamino sulfur trifluoride (DAST, 30 mL, 227 mmol) at 0 °C. The mixture was stirred for 12 h at 40 °C. Five additional reactions of 0.5 g, 2 g, and 3 g (three reactions) were carried out as described above. The reactions were combined and quenched with saturated NaHCO ₃ (800 mL) at 20 °C. The mixture was then diluted with water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (9.5 g, 16.5 mmol, yield 56.7%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.44-1.55 (m, 9H), 3.60-3.74 (m, 3H), 3.86-3.96 (m, 1H), 4.13 (k, J= 7.09 Hz, 2H), 4.45-4.59 (m, 1H), 4.66 (lat d, J= 16.88 Hz, 2H), 5.08-5.24 (m, 2H), 7.18 (br.s, 1H), 7.31-7.48 (m, 5H).

Example 127M: tert-butyl 6-(benzyloxy)-4,4,8-trifluoro-7-[(2-methoxy-2-oxoethyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00573] To a solution of the product of Example 127L (9 g, 14.05 mmol) in methanol (90 mL) was added K ₂ CO ₃ (3.88 g, 28.1 mmol) at 20 °C. The mixture was stirred for 1 h at 20 °C. Two additional reactions were carried out at 0.5 g and 4.5 g as described above. The reaction mixtures were combined, diluted with water (200 mL), and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (7.9 g, 16.4 mmol, 90% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.51 (s, 9H), 3.75 (s, 3H), 3.97 (br t, J= 10.82 Hz, 2H), 4.06-4.26 (m, 2H), 4.59 (br s, 2H), 4.77 (br s, 1H), 5.13 (s, 2H), 6.86-7.10 (m, 1H), 7.31-7.53 (m, 5H).

Example 127N: tert-butyl 6-(benzyloxy)-4,4,8-trifluoro-7-[(2-methoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00574] To a solution of chlorosulfonyl isocyanate (0.854 mL, 9.83 mmol) in dichloromethane (5 mL) was added dropwise allyl alcohol (0.669 mL, 9.83 mmol) at 0 °C. The mixture was stirred for 30 min at 0 °C. To the above mixture was added dropwise a solution of the product of Example 127M (3.5 g, 6.56 mmol) and N,N -diisopropylethylamine (2.290 mL, 13.11 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C. The mixture was diluted with water (10 mL). _The organic phase was separated, dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (6 g, crude), which was used in the next step without further purification. MS (ESI ⁺ ) m/z 666 [M+Na] ⁺ .

Example 127O: tert-butyl 6-(benzyloxy)-4,4,8-trifluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00575] To a solution of the product of Example 127N (6 g, 6.53 mmol) in anhydrous methanol (5 mL) were added K ₂ CO ₃ (2.98 g, 21.53 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.226 g, 0.196 mmol) at 20 °C under N ₂ . The mixture was stirred at 20 °C under N ₂ for 12 h. The mixture was filtered, the filtrate was diluted with water (20 mL), adjusted to pH = 3 with aqueous HCl (1 mol/L), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:methanol=10:1) to give the title compound (2.1 g, 4.0 mmol, yield 53.2%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.33-1.50 (m, 1H), 1.45 (s, 8H), 3.19 (s, 2H), 3.76-4.03 (m, 1H), 4.04-4.21 (m, 4H), 4.58 (br. s, 2H), 5.24 (s, 2H), 7.20 (s, 1H), 7.26-7.42 (m, 1H), 7.31-7.42 (m, 1H), 7.31-7.42 (m, 1H), 7.31-7.42 (m, 1H), 7.52 (d, J= 7.13 Hz, 2H); MS (IER ^- ) m/z 526 [MH] ^- .

Example 127P : 5-[6-(benzyloxy)-4,4,8-trifluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00576] To a solution of the product of Example 127O (200 mg, 0.341 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) dropwise at 0 °C. The mixture was stirred for 1 h at 20 °C. The mixture was concentrated under reduced pressure to give the title compound as a trifluoroacetic acid salt (160 mg, 99% yield), which was used in the next step without further purification. MS (ESI ^- ) m/z 426 [MH] ^- .

Example 127Q: 5-[6-(benzyloxy)-2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl]ethyl}-4,4,8-trifluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00577] To a solution of the product of Example 127P (150 mg, 0.316 mmol) in 1,2-dichloroethane (2 mL) was added triethylamine (0.088 mL, 0.632 mmol), followed by a solution of the product of Example 127E (106 mg, 0.474 mmol) in 1,2-dichloroethane (2 mL) at 20 °C. After 10 min, sodium triacetoxyborohydride (167 mg, 0.790 mmol) was added and the mixture was stirred at 20 °C for 12 h. The mixture was diluted with saturated NaHCO ₃ (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to give the title compound (90 mg, 0.15 mmol, yield 41.8%). MS (ESI ^- ) m/z 612 [MH] ^- .

Example 127R: 5-(2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl]ethyl}-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ 6,2,5-thiadiazolidine-1,1,3-trione

[00578] To a mixture of the product of Example 127Q (90 mg, 0.132 mmol) in dichloromethane (1 mL) was added pentamethylbenzene (58.7 mg, 0.396 mmol) at 20 °C. The mixture was cooled to -78 °C under N ₂ before adding boron trichloride (1.056 mL, 1.056 mmol). The mixture was then stirred for 10 min at -78 °C and 1 h at 0 °C. The reaction was then quenched at -78 °C by the dropwise addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC on a ^Phenomenex® C18 Gemini-NX 3 μm 150×30 mm column eluting with a gradient of acetonitrile (A) _and 10 mM _NH4HCO3 in water (B) at a flow rate of 25 mL/min (0-8 min linear gradient 30-60% A, 8-10 min 100% A) to give the title compound (3.3 mg, 0.006 mmol, 4.6% yield). ¹ H NMR (400 MHz, _methanol-d4 ) δ ppm. 2.22 (lat. d, J= 19.14 Hz, 6 H) 2.70 (lat. s, 4 H) 3.24 (lat. s, 2 H) 3.78 (lat. s, 2 H) 4.23-4.46 (m, 4 H) 5.83-6.24 (m, 1 H) 7.01 (lat. s, 1 H); MS (IER ^- ) m/z 522 [MH] ^- .

Example 128: 5-(4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]methyl}-3,5-dimethyl-1 H -pyrazol-1-yl)-2,2-dimethylpentanenitrile (Compound 227)

Example 128A: 5-(4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}-3,5-dimethyl-1H-pyrazol-1-yl)-2,2-dimethylpentanenitrile

[00579] To a vial containing the product of Example 93A (0.15 mmol theoretical) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 10 min, then 5-(4-formyl-3,5-dimethyl- 1H- pyrazol-1-yl)-2,2-dimethylpentanenitrile (0.054 g, 0.23 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 14 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (25 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 15 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.081 g, 0.13 mmol, 87% yield). ¹ H NMR (600 MHz, DMSO -d ₆ ) δ ppm. 9.50 (br s, 1H), 7.50-7.45 (m, 2H), 7.38-7.31 (m, 2H), 7.31-7.22 (m, 1H), 6.89 (s, 1H), 5.17 (s, 2H), 4.48 (br d, J = 15.0 Hz, 1H), 4.38 (br d, J = 14.0 Hz, 1H), 4.24 (br d, J = 13.6 Hz, 1H), 4.17 (br d, J = 13.6 Hz, 1H), 4.04-3.99 (m, 2H), 3.99-3.91 (m, 2H), 3.58 (br s, 1H), 3.30 (br s, 1H), 3.03 (br s, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 1.93-1.75 (m, 2H), 1.62-1.43 (m, 2H), 1.28 (s, 6H); MS (APCI ⁺ ) m/z 609.4 [M+H] ⁺ .

Example 128B: 5-(4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}-3,5-dimethyl-1H-pyrazol-1-yl)-2,2-dimethylpentanenitrile

[00580] A vial containing a suspension of 5-(4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]methyl}-3,5-dimethyl-1 H -pyrazol-1-yl)-2,2-dimethylpentanenitrile (0.077 g, 0.13 mmol, Example 128A) and 1,2,3,4,5-pentamethylbenzene (0.056 g, 0.38 mmol) in dichloromethane (1.3 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.0 mL, 1.0 mmol) was then added slowly. The resulting mixture was stirred at -78 °C for 10 min, then the dry ice-acetone bath was replaced with an ice/water bath. After 60 min, the mixture was cooled again to -78 °C and quenched by the successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.059 g, 0.11 mmol, 90% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 9.73 (br s, 1H), 9.61 (s, 1H), 6.55 (s, 1H), 4.14 (br s, 4H), 4.00 (t, J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.26 (br s, 2H), 2.96 (t, J = 5.4 Hz, 2H), 2.28 (s, 3H), 2.18 (s, 3H), 1.87-1.79 (m, 2H), 1.55-1.47 (m, 2H), 1.28 (s, 6H); MS (APCI ⁺ ) m/z 519.2 [M+H] ⁺ .

Example 129: 5-{8-fluoro-6-hydroxy-2-[(piperidin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 228)

Example 129A: tert-butyl 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]methyl}piperidine-1-carboxylate

[00581] Triethylamine (0.083 mL, 0.594 mmol) was added to the product of Example 65A (150 mg, 0.297 mmol) in dichloromethane (1 mL) and the mixture was stirred at ambient temperature for 5 min. Tert -butyl 4-formylpiperidine-1-carboxylate (130 mg, 0.610 mmol) in dichloromethane (1 mL) was then added and the resulting mixture was stirred for an additional 10 min. Sodium triacetoxyhydroborate (157 mg, 0.742 mmol) was then added and the reaction mixture was stirred at ambient temperature for 15 h. The reaction mixture was diluted with dichloromethane and stirred with saturated sodium bicarbonate (20 mL) for 20 min. The mixture was extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, flow rate 50 mL/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with _CO2 (s)]) twice to give the title compound (111.7 mg, 0.190 mmol, 63.9% yield). MS ( ^APCI ) m/z 590 [M+H] ⁺ .

Example 129B: 5-{8-fluoro-6-hydroxy-2-[(piperidin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00582] Trichloroborane (1.0 M in dichloromethane, 679 µL, 0.679 mmol) was added to a vial containing a suspension of the product of Example 129A (50 mg, 0.085 mmol) and 1,2,3,4,5-pentamethylbenzene (37.8 mg, 0.255 mmol) in dichloromethane (849 µL) cooled to -78 °C. The resulting mixture was stirred at -78 °C for 30 min and then quenched with ethanol (4 mL). The mixture was then warmed to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (Agel Technologies Claricep™ Flash C18 100 40-60 μm, flow rate 50 ml/min, 10 to 100% methanol in water, 120 g [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with CO ₂ (s)]) to give the title compound (6.5 mg, 0.016 mmol, 19.2% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 6.44 (s, 1H), 3.93 (s, 2H), 3.41 (s, 2H), 3.23 (dt, J =12.7, 3.4 Hz, 2H), 2.86 (td, J =12.6, 2.9 Hz, 2H), 2.71 (t, J =5.8 Hz, 2H), 2.60 (t, J =5.8 Hz, 2H), 2.34 (d, J =7.0 Hz, 2H), 1.94-1.86 (m, 2H), 1.84 (d, J =3.6 Hz, 1H), 1.28-1.18 (m, 2H); MS (CIAD ⁺ ) m/z 399 [M+H] ⁺ .

Example 130: 5-{8-fluoro-6-hydroxy-2-[3-(morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 229)

Example 130A: 5-{6-(benzyloxy)-8-fluoro-2-[3-(morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00583] To a vial containing a suspension of the product of Example 65A (150 mg, 0.297 mmol) in acetonitrile (2.5 mL) were added potassium carbonate (205 mg, 1.484 mmol) and 3-morpholinopropyl methanesulfonate (133 mg, 0.594 mmol). The reaction mixture was heated to 60 °C for 2 h. The reaction mixture was filtered through a pad of diatomaceous earth, eluting sequentially with acetonitrile and methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (120 g Agela Technologies Claricep™ Flash C18 100 40-60 μm, flow rate 50 ml/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO ₂ (s)]) to give the title compound (43.2 mg, 0.083 mmol, yield 28.1%). ¹ H NMR (600 MHz, DMSO -d ₆ ) δ ppm. 7.52-7.47 (m, 2H), 7.35 (dd, J =8.2, 6.7 Hz, 2H), 7.32-7.26 (m, 1H), 6.77 (s, 1H), 5.12 (s, 2H), 3.95 (s, 2H), 3.67 (s, 4H), 2.88-2.85 (m, 3H), 2.77-2.65 (m, 11H), 1.85 (s, 2H); MS (CIAD ⁺ ) m/z 519 [M+H] ⁺ .

Example 130B: 5-{8-fluoro-6-hydroxy-2-[3-(morpholin-4-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00584] Trichloroborane (1.0 M in dichloromethane, 614 µL, 0.614 mmol) was added to a vial containing a suspension of Example 130A and 1,2,3,4,5-pentamethylbenzene (34.1 mg, 0.230 mmol) in dichloromethane (767 µL) cooled to -78 °C. The resulting mixture was stirred at -78 °C for 1 hour and then at 0 °C for 30 minutes. The mixture was again cooled to -78 °C and quenched with ethanol (4 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 minutes. The mixture was then concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Agel Technologies Claricep™ Flash C18 100 column) 40-60 μm, 120 g, flow rate 50 ml/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO ₂ (s)]) to give the title compound (19.7 mg, 0.046 mmol, 59.9% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 9.39 (s, 1H), 6.52 (s, 1H), 3.94 (s, 2H), 3.83 (s, 2H), 3.67 (d, J =4.8 Hz, 4H), 3.01 (s, 2H), 2.88-2.84 (m, 3H), 2.82 (s, 5H), 2.77 (s, 2H), 1.90 (t, J =7.2 Hz, 2H); MS (CIAD ⁺ ) m/z 429 [M+H] ⁺ .

Example 131: 5-{8-fluoro-6-hydroxy-2-[2-(piperidin-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 230)

Example 131A: tert-butyl 4-{2-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}piperidine-1-carboxylate

[00585] Triethylamine (0.083 mL, 0.594 mmol) was added to 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate (150 mg, 0.297 mmol, Example 54A) in dichloromethane (5 mL) and the mixture was stirred at ambient temperature for 5 min. Tert -butyl 4-(2-oxoethyl)piperidine-1-carboxylate (130 mg, 0.572 mmol) was then added and the mixture was stirred for an additional 10 min. Sodium triacetoxyhydroborate (157 mg, 0.742 mmol) was then added and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with dichloromethane (5 mL) and stirred with saturated sodium bicarbonate (20 mL) for 20 min. The mixture was extracted with dichloromethane. The organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Agel Technologies Claricep™ Flash C18 100 40-60 μm, 120 g, flow rate 50 ml/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO ₂ (s)]) to give the title compound (173.2 mg, 0.287 mmol, 97% yield). MS (APCI ⁺ ) m/z 603 [M+H] ⁺ .

Example 131B: 5-{8-fluoro-6-hydroxy-2-[2-(piperidin-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00586] Trichloroborane (1.0 M in dichloromethane, 929 µL, 0.929 mmol) was added to the vial, followed by a suspension of the product of Example 131A (51.7 mg, 0.348 mmol) in dichloromethane (1161 µL) cooled to -78 °C. The mixture was stirred at -78 °C for 10 min and then at 0 °C for 20 min. The reaction mixture was again cooled to -78 °C and quenched by adding ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for an additional 15 min. The mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (120 g Agela Technologies Claricep™ Flash C18 100 column) 40-60 μm, flow rate 50 ml/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with CO ₂ (s)] to give the title compound (10.3 mg, 0.025 mmol, yield 21.5%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 6.44 (s, 1H), 3.93 (s, 2H), 3.21 (d, J = 12.8 Hz, 3H), 2.82 (t, J = 12.5 Hz, 2H), 2.70 (d, J = 5.7 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H), 1.82 (d, J = 13.6 Hz, 2H), 1.62 (s, 2H), 1.47 (q, J = 7.5, 7.1 Hz, 2H), 1.30-1.29 (m, 3H); MS (APCI ⁺ ) m/z 413 [M+H] ⁺ .

Example 132: 5-(8-fluoro-6-hydroxy-2-{2-[(1 s ,3 r )-3-(trifluoromethoxy)cyclobutyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 231)

Example 132A: 5-[6-(benzyloxy)-8-fluoro-2-{2-[(1s,3r)-3-(trifluoromethoxy)cyclobutyl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7- yl]-1 λ ^6,2,5 -thiadiazolidine-1,1,3-trione, ammonium salt

[00587] A suspension of the product of Example 135H (120.0 mg, 0.356 mmol, 1.4 equivalents), 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominal 0.254 mmol, 1 equivalent, Example 54A), and potassium carbonate (176 mg, 1.27 mmol, 5.0 equivalents) in acetonitrile (0.8 mL) was placed in a heating block that had been preheated to 60 °C. The reaction mixture was stirred for 18 hours at 60 °C. The reaction mixture was cooled to 23 °C. The cooled reaction mixture was diluted with dimethyl sulfoxide (1 mL) and saturated aqueous ammonium chloride (0.5 mL). The diluted mixture was purified by reverse-phase flash column chromatography (50 g ^RediSep® Gold C18 column, eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (35 mg, 0.061 mmol, 25% yield, two steps). MS (APCI ⁾ m / z 558 [M+H] ⁺ .

Example 132B: 5-(8-fluoro-6-hydroxy-2-{2-[(1s,3r)-3-(trifluoromethoxy)cyclobutyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00588] A suspension of palladium on carbon (10 wt %, 6.7 mg, 0.006 mmol, 10.0 mol %), ammonium formate (20 mg, 0.314 mmol, 5.0 equivalents), and the product of Example 132A (35 mg, 0.063 mmol, 1 equivalent) in ethanol (1.0 mL) was stirred for 2 hours at 23 °C. Additional ammonium formate (58 mg, 0.920 mmol, 14.6 equivalents) was added at 23 °C. The reaction mixture was stirred for 30 minutes at 23 °C. Additional palladium on carbon (10 wt %, 15.0 mg, 0.014 mmol, 22.3 mol %) was added at 23 °C. The reaction mixture was stirred for 1 h at 23 °C. Water (0.2 mL) was added at 23 °C. The reaction vessel was then placed in a heating block preheated to 40 °C. The reaction mixture was stirred for 1 h at 40 °C. The reaction mixture was then cooled to 23 °C. The cooled mixture was filtered through a pad of diatomaceous earth (1.0 cm × 0.5 cm). The filter cake was washed with methanol (3 × 1.0 mL). The filtrates were combined and concentrated. The resulting residue was purified by reverse phase flash column chromatography (5.5 g RediSep Rf Gold ^® C18 column, eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 13 mL/min) to give the title compound (20 mg, 0.041 mmol, 66% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.67 (br, 1H), 6.57 (s, 1H), 4.68 (p, J =7.4 Hz, 1H), 4.56-4.02 (m, 2H), 3.94 (s, 2H), 3.79-3.46 (m, 1H), 3.24-2.89 (m, 5H), 1.88 (aps. s, 5H); MS (CIAD ⁺ ) m/z 468 [M+H] ⁺ .

Example 133: 5-{8-fluoro-6-hydroxy-2-[3-(4-methylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 232)

Example 133A: 5-{6-(benzyloxy)-8-fluoro-2-[3-(4-methylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00589] To a vial containing a suspension of the product of Example 65A in acetonitrile (2 mL) (150 mg, 0.297 mmol) were added potassium carbonate (205 mg, 1.484 mmol) and 1-(3-bromopropyl)-4-methylpiperazine 2 hydrobromic acid (162 mg, 0.297 mmol) and stirred at 60 °C for 3 hours. The solution was filtered through a pad of diatomaceous earth, eluting with acetonitrile. The filtrate was concentrated under reduced pressure. The product was purified by reverse phase column chromatography (120 g Agela Technologies Claricep™ Flash C18 100 40-60 μm, flow rate 50 ml/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO ₂ (s)]) to give the title compound (49.1 mg, 0.092 mmol, 31.1% yield). MS (APCI ⁺ ) m/z 532 [M+H] ⁺ .

Example 133B: 5-{8-fluoro-6-hydroxy-2-[3-(4-methylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00590] Trichloroborane (1.0 M in dichloromethane, 584 μL, 0.584 mmol) was added to a vial containing a suspension of the product of Example 133A (38.8 mg, 0.073 mmol) and 1,2,3,4,5-pentamethylbenzene (32.5 mg, 0.219 mmol) in dichloromethane (730 μL) and cooled to -78 °C. The mixture was stirred at -78 °C for 10 min and then at 0 °C for 20 min. The mixture was cooled again to -78 °C, diluted with dichloromethane (2 mL), and quenched by the successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was warmed to room temperature and stirred for 15 min. The mixture was diluted with ethanol and concentrated under reduced pressure. The compound was purified by reversed-phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 50 mL/min flow rate, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with _CO2 (s)]) to afford the title compound (16.8 mg, 0.038 mmol, 52.1% yield). ¹ H NMR (500 MHz, _DMSO-d6 ) δ ppm 9.21 (s, 1H), 6.46 (s, 1H), 3.94 (s, 2H), 3.50 (s, 2H), 3.17 (s, 1H), 2.80 (s, 8H), 2.75 (d, J =6.2 Hz, 2H), 2.75-2.54 (m, 6H), 2.46 (s, 3H), 1.75 (n, J =7.2 Hz, 2H); MS (CIAD ⁺ ) m/z 442 [M+H] ⁺ .

Example 134: 5-(8-fluoro-6-hydroxy-2-{2-[(propan-2-yl)oxy]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 233)

Example 134A: 5-[6-(benzyloxy)-8-fluoro-2-{2-[(propan-2-yl)oxy]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00591] To a vial containing a suspension of the product of Example 65A (100 mg, 0.198 mmol) in acetonitrile (2 mL) was added potassium carbonate (137 mg, 0.989 mmol). The resulting solution was stirred at ambient temperature for 10 minutes. 2-Isopropoxyethyl methanesulfonate (54.1 mg, 0.297 mmol) dissolved in acetonitrile (0.5 mL) was then added and the resulting mixture was heated to 60 °C for 17 hours. The solution was filtered through a pad of diatomaceous earth, eluting with acetonitrile and methanol. The filtrate was concentrated under reduced pressure. The product was purified by reverse phase column chromatography (Agel Technologies Claricep™ Flash C18 100 column) 40-60 μm, 120 g, flow rate 50 ml/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO ₂ (s)]) to give the title compound (16.2 mg, 0.034 mmol, 17.15% yield). MS (APCI ⁺ ) m/z 478 [M+H] ⁺ .

Example 134B: 5-(8-fluoro-6-hydroxy-2-{2-[(propan-2-yl)oxy]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00592] Trichloroborane (1.0 M in dichloromethane, 271 μL, 0.271 mmol) was added to a vial containing a suspension of the product of Example 134A (16.2 mg, 0.034 mmol) and 1,2,3,4,5-pentamethylbenzene (15.09 mg, 0.102 mmol) in dichloromethane (339 μL) cooled to -78 °C. The resulting mixture was stirred at -78 °C for 30 min. The mixture was diluted with ethanol (1 mL), then warmed to ambient temperature and stirred for an additional 15 min. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH ₇ with _CO2 (s)]) to give the title compound (5.6 mg, 0.014 mmol, 42.6% yield). ¹ H NMR (500 MHz, DMSO- d6 ) δ ppm 9.59 (s, 1H), 6.55 (s, 1H), 4.14 (s, 2H), 3.94 (s, 2H), 3.72 (t, J =5.1 Hz, 2H), 3.63 (p, J =6.1 Hz, 1H), 3.25 (s, 2H), 2.95 (t, J =6.2 Hz, 2H), 1.13 (d, J =6.1 Hz, 6H); MS (CIAD ⁺ ) m/z 388 [M+H] ⁺ .

Example 135: 5-[1-fluoro-3-hydroxy-7-({2-[(1 s ,3 r )-3-(trifluoromethoxy)cyclobutyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 234)

Example 135A: benzyl (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylate

[00593] To a mixture of solid silver trifluoromethanesulfonate (394 g, 1536 mmol), 1-chloromethyl 4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (204 g, 576 mmol) and potassium fluoride (89.2 g, 1536 mmol) was added a solution of benzyl(1 s ,3 s )-3-hydroxycyclobutane-1-carboxylate (88 g, 90% purity by ¹ H NMR, 384 mmol) in ethyl acetate (1800 mL), then 2-fluoropyridine (132 mL, 1536 mmol) and (trifluoromethyl)trimethylsilane (274 g, 960 mmol) dropwise. After 36 h, the reaction mixture was filtered through ^Celite® and concentrated in vacuo to give a crude product which was purified by column chromatography eluting with petroleum ether:ethyl acetate 20:1 to give the title compound (90 g, 90% pure by ¹ H NMR, 295 mmol, 76.8% yield). ¹ H NMR (400 MHz, _CDCl3 ) δ ppm. 7.43-7.32 (m, 5H), 5.15 (s, 2H), 4.58 (p, J =7.5 Hz, 1H), 2.87-2.70 (m, 1H), 2.65 (dtd, J =9.6, 7.3, 2.6 Hz, 2H), 2.60-2.49 (m, 2H), 1.27 (t, J =7.1 Hz, 1H).

Example 135B: (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid

[00594] To a solution of the product of Example 135A (90 g, 90% pure by ¹ H NMR, 295 mmol) in tetrahydrofuran (500 mL) was added palladium(II) hydroxide on carbon (30 g, 214 mmol) and the reaction mixture was placed under hydrogen gas (15 psi). After 1 h, the reaction mixture was vented and then filtered through ^Celite® . The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a mixture of petroleum ether and ethyl acetate 20:1 to give the title compound (60 g, 90% pure by ¹ H NMR, 293 mmol, 99% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 11.66 (br s, 1H), 4.60 (p, J =7.4 Hz, 1H), 2.85-2.62 (m, 3H), 2.61-2.49 (m, 2H).

Example 135C: [(1s,3s)-3-(trifluoromethoxy)cyclobutyl]methanol

[00595] To a solution of the product of Example 135B (30.0 g, 90% pure by ¹ H NMR, 146 mmol) in tetrahydrofuran (600 mL) at 0 °C was added lithium aluminum hydride (6.68 g, 176 mmol) portionwise. After 30 min, the reaction was quenched with water (5 mL) and stirred for 5 min, then 15% aqueous sodium hydroxide (5 mL) was added, followed by water (15 mL). The mixture was filtered through ^Celite® , and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a mixture of petroleum ether and ethyl acetate 20:1 to give the title compound (17.00 g, 90% pure by ¹ H NMR, 90 mmol, 61.6% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.57 (p, J = 7.4 Hz, 1H), 3.65 (d, J = 5.5 Hz, 2H), 2.55-2.37 (m, 2H), 2.19-1.93 (m, 3H), 1.43 (br s, 1H).

Example 135D: [(1s,3s)-3-(trifluoromethoxy)cyclobutyl]methyl 4-methylbenzene-1-sulfonate

[00596] To a solution of the product of Example 135C (17 g, 90 mmol, 90% purity) in dichloromethane (400 mL) at 0 °C was added triethylamine (21.84 g, 216 mmol), followed by 4-toluenesulfonyl chloride (25.7 g, 135 mmol) in portions. After 12 h, the reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column purification eluting with a mixture of petroleum ether and ethyl acetate 20:1 to give the title compound (28.00 g, 86.3 mmol, 95.9% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.80 (d, J =8.3 Hz, 2H), 7.37 (d, J =8.1 Hz, 2H), 4.52 (p, J =7.5 Hz, 1H), 4.01 (d, J =6.0 Hz, 2H), 2.52-2.38 (m, 5H), 2.31-2.17 (m, 1H), 2.04-1.88 (m, 2H).

Example 135E: [(1s,3r)-3-(trifluoromethoxy)cyclobutyl]acetonitrile

[00597] To a solution of the product of Example 135D (19 g, 55.7 mmol) in dimethyl sulfoxide (200 mL) was added sodium cyanide (3.27 g, 66.8 mmol). After 12 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (10.6 g, 90% purity by ¹ H NMR, 49.2 mmol, 88.3% yield), which was used in the next step without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.54 (p, J =7.4 Hz, 1H), 2.72-2.60 (m, 2H), 2.52 (d, J =6.4 Hz, 2H), 2.31-2.17 (m, 1H), 2.14-2.05 (m, 2H).

Example 135F: [(1S,3s)-3-(trifluoromethoxy)cyclobutyl]acetic acid

[00598] To a solution of the product of Example 135E (10.6 g, 90% purity by ¹ H NMR, 49.2 mmol) in a mixture of water (90 mL) and methanol (90 mL) was added sodium hydroxide (39.4 g, 985 mmol), and the resulting mixture was heated to 100 °C. After 12 h, the reaction mixture was cooled to ambient temperature, diluted with water (100 mL), and washed with ethyl acetate (200 mL). The aqueous layer was adjusted to pH 3 with 1 M hydrochloric acid and then extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (12 g, 48.5 mmol, 80% purity, 98% yield), which was used without purification in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.53 (p, J =7.5 Hz, 1H), 2.62 (dtd, J =9.6, 7.0, 3.1 Hz, 2H), 2.53 (d, J =7.4 Hz, 2H), 2.33-2.19 (m, 1H), 2.02-1.90 (m, 2H).

Example 135G: 2-[(1s,3r)-3-(trifluoromethoxy)cyclobutyl]ethan-1-ol

[00599] To a solution of the product of Example 135F (11 g, 80% purity by ¹ H NMR, 44.4 mmol) in tetrahydrofuran (110 mL) at 0 °C was added a solution of the borane complex of tetrahydrofuran (89 mL, 1 M in tetrahydrofuran, 89 mmol) in portions. After 30 min, the reaction mixture was warmed to room temperature and stirred for 12 h, then quenched with methanol (100 mL). The mixture was concentrated in vacuo and the residue was purified by column chromatography eluting with a mixture of petroleum ether and ethyl acetate 20:1 to give the title compound (7.50 g, 38.7 mmol, 91.7% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 4.51 (p, J =7.4 Hz, 1H), 3.62 (t, J =6.5 Hz, 2H), 2.59-2.48 (m, 2H), 2.04-1.93 (m, 1H), 1.93-1.83 (m, 2H), 1.72 (k, J =6.8 Hz, 2H), 1.42-1.21 (m, 1H).

Example 135H: 2-[(1s,3r)-3-(trifluoromethoxy)cyclobutyl]ethyl 4-methylbenzene-1-sulfonate

[00600] To a solution of the product of Example 135G (3.50 g, 18.06 mmol) in dichloromethane (30 mL) at 0 °C was added triethylamine (6.04 mL, 43.3 mmol), followed by p-toluenesulfonyl chloride (5.16 g, 27.1 mmol) portionwise. After 12 h, the reaction was quenched with water (30 mL) and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with petroleum ether:ethyl acetate 20:1 to give the title compound (5.74 g, 14.93 mmol, 93.9% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.79 (d, J =8.3 Hz, 2H), 7.36 (d, J =8.0 Hz, 2H), 4.46 (p, J =7.4 Hz, 1H), 3.99 (t, J =6.1 Hz, 2H), 2.54-2.37 (m, 5H), 1.99-1.87 (m, 1H), 1.86-1.75 (m, 4H).

Example 135I: 2-[(1s,3r)-3-(trifluoromethoxy)cyclobutyl]ethan-1-amine

[00601] To a solution of the product of Example 135H (0.5487 g, 1.622 mmol) and di- tert- butyl iminodicarboxylate (3.88 g, 1.784 mmol) in N,N -dimethylformamide (5.5 mL) was added cesium carbonate (0.793 g, 2.43 mmol), and the resulting mixture was heated to 60 °C. After 17 h, the mixture was cooled to ambient temperature, quenched with saturated aqueous ammonium chloride (2.25 mL), diluted with water (5.5 mL), and extracted with ethyl acetate (3 x 5.5 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3 x 5.5 mL) and brine (2.25 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate (5.5 mL) and hydrogen chloride solution (5.5 mL, 4 M in dioxane, 22 mmol) was added. After 3 days, the mixture was concentrated, then ethyl acetate (5.5 mL) was added. The resulting solid was collected by filtration, washed with ethyl acetate (2.25 mL) and dried in a vacuum oven at 50 °C to give the title compound as a hydrochloride salt (0.285 g, 1.298 mmol, 80% yield). ¹ H NMR (500 MHz, methanol -d ₄ ) δ ppm. 4.62 (p, J = 7.4 Hz, 1H), 2.89-2.82 (m, 2H), 2.63-2.53 (m, 2H), 2.10-1.83 (m, 3H), 1.83-1.73 (m, 2H); MS (APCI ⁺ ) m/z 184 [M+H] ⁺ .

Example 135J: 5-[3-(benzyloxy)-1-fluoro-7-({2-[(1s,3r)-3-(trifluoromethoxy)cyclobutyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00602] To a solution of the product of Example 67F (0.350 g, 0.865 mmol) in ethanol (6 mL) was added triethylamine (0.362 mL, 2.60 mmol), followed by the product from Example 135I (0.285 g, 1.298 mmol). After 30 min, sodium cyanoborohydride (0.065 g, 1.039 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.088 mL, 5.19 mmol), then diluted with acetonitrile (10 mL) and water (2 mL). ^Celite® (4 g) was added and the mixture was concentrated in vacuo to give a powder. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.3830 g, 0.670 mmol, 77.0% yield). MS ( ^APCI ) m/z 572 [M+H] ⁺ .

Example 135K: 5-[1-fluoro-3-hydroxy-7-({2-[(1s,3r)-3-(trifluoromethoxy)cyclobutyl]ethyl}amino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00603] To a suspension of the product of Example 135J (0.3830 g, 0.670 mmol) and pentamethylbenzene (0.199 g, 1.34 mmol) in dichloromethane (7.6 mL) at -78 °C was added a solution of boron trichloride (4.02 mL, 1 M, in dichloromethane, 4.02 mmol) slowly down the side of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (4 mL) and then ethanol (4 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 8 mL), ethyl acetate/heptane (1:1) (2 x 8 mL), and dichloromethane (2 x 8 mL) to give a gum, which was dissolved in methanol (20 mL). ^Celite® (3 g) was added and the mixture was concentrated in vacuo to give a powder. The resulting mixture was dry loaded onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.2012 g, 0.418 mmol, 62.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.25 (s, 1H), 8.49 (br s, 2H), 6.47 (s, 1H), 4.68 (p, J = 7.2 Hz, 1H), 3.94 (s, 2H), 3.47-3.32 (m, 3H), 3.08 (dd, J = 15.9, 5.4 Hz, 1H), 2.99-2.91 (m, 2H), 2.77 (ct, J =16.8, 7.8 Hz, 2H), 2.57-2.51 (m, 1H), 2.19-2.11 (m, 1H), 1.99-1.81 (m, 3H), 1.82-1.72 (m, 2H), 1.68 (dg, J =11.4, 5.7 Hz, 1H); MS (CIAD ⁺ ) m/z 482 [M+H] ⁺ .

Example 136: 5-(1-fluoro-3-hydroxy-7-{[(1 s ,3 s )-3-(trifluoromethoxy)cyclobutyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 235)

Example 136A: tert-butyl [(1s,3s)-3-(trifluoromethoxy)cyclobutyl]carbamate

[00604] To a solution of the product of Example 135B (12 g, 58.7 mmol, 90% purity) in toluene was added triethylamine (16.35 mL, 117 mmol) followed by diphenylphosphoryl azide (18.96 mL, 88 mmol). After 30 min, tert-butanol (360 mL) was added and the resulting mixture was heated to 110 °C. After 18 h, the reaction mixture was cooled to ambient temperature and then concentrated in vacuo. The residue was purified by column chromatography eluting with a mixture of petroleum ether and ethyl acetate 10:1 to give the title compound (16.00 g, 80% purity based on ¹ H NMR, 50.2 mmol). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 4.58 (br s, 1H), 4.29 (p, J =7.2 Hz, 1H), 3.75 (br s, 1H), 2.76 (br d, J =6.8 Hz, 1H), 2.08-1.91 (m, 1H), 1.37 (s, 9H).

Example 136B: (1s,3s)-3-(trifluoromethoxy)cyclobutan-1-amine

[00605] To a solution of hydrogen chloride (320 mL, 4 M in ethyl acetate, 1280 mmol) was added the product of Example 136A (14 g, 80% pure by ¹ H NMR, 50.2 mmol). After 4 h, the reaction mixture was concentrated in vacuo. The residue was triturated with methyl tert -butyl ether (25 mL) to give the title compound as the hydrochloride salt (8.1 g, 42.3 mmol, 84.2% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 8.38 (br s, 3H), 4.66 (p, J = 7.2 Hz, 1 H), 3.28-3.35 (m, 1H), 2.65-2.78 (m, 2H), 2.30-2.45 (m, 2H); MS (ESI ⁺ ) m/z 156 [M+H] ⁺ .

Example 136C: 5-[3-(benzyloxy)-1-fluoro-7-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl] -1 λ ^6,2,5 -thiadiazolidine-1,1,3-trione

[00606] To a solution of the product of Example 67F (0.285 g, 0.705 mmol) in ethanol (5.7 mL) was added triethylamine (0.295 mL, 2.12 mmol), followed by the product from Example 136B (0.2025 g, 1.057 mmol). After 30 min, sodium cyanoborohydride (0.053 g, 0.846 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.080 mL, 4.23 mmol), then diluted with acetonitrile (10 mL) and water (2 mL). ^Celite® (4 g) was added and the mixture was concentrated in vacuo to give a powder. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.2553 g, 0.470 mmol, 66.6% yield). MS ( ^APCI ) m/z 544 [M+H] ⁺ .

Example 136D: 5-(1-fluoro-3-hydroxy-7-{[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00607] To a suspension of the product of Example 136C (0.2553 g, 0.470 mmol) and pentamethylbenzene (0.139 g, 0.939 mmol) in dichloromethane (5 mL) at -78 °C was added a solution of boron trichloride (2.82 mL, 1 M in dichloromethane, 2.82 mmol) slowly down the side of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (2.5 mL) and then ethanol (2.5 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 5 mL), ethyl acetate/heptane (1:1) (2 x 5 mL), and dichloromethane (2 x 5 mL) to give a solid which was dissolved in methanol (20 mL). ^Celite® (3 g) was added and the mixture was concentrated in vacuo to give a powder. The resulting mixture was dry loaded onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.1761 g, 0.388 mmol, 83.0% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.13 (s, 1H), 7.13 (br. s, 2H), 6.45 (s, 1H), 4.60 (p, J = 7.3 Hz, 1H), 3.94 (s, 2H), 3.5-3.3 (m, 1H), 3.12 (s, 1H), 2.91 (dd, J = 16.2, 5.3 Hz, 1H), 2.81-2.63 (m, 4H), 2.36 (dd, J =16.5, 9.4 Hz, 1H), 2.21 (s, 2H), 1.95 (d, J =25.7 Hz, 1H), 1.56 (dt, J =15.8, 10.8 Hz, 1H); MS (CIAD ⁺ ) m/z 454 [M+H] ⁺ .

Example 137: 5-(8-fluoro-6-hydroxy-2-{1-[(1,3,5-trimethyl-1H - pyrazol-4-yl)methyl]piperidin-4-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 236)

Example 137A: tert-butyl 4-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]piperidine-1-carboxylate

[00608] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate (theoretical 0.407 mmol) were added 1,2-dichloroethane (2.0 mL) and triethylamine (0.11 mL, 0.81 mmol). The mixture was stirred for 10 min, then tert -butyl 4-oxopiperidine-1-carboxylate (0.122 g, 0.611 mmol) was added. After 60 min, sodium triacetoxyhydroborate (0.216 g, 1.02 mmol) was added. After 96 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.177 g, 0.308 mmol, 76% yield over two steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 9.75 (br s, 1H), 7.52-7.47 (m, 2H), 7.38-7.32 (m, 2H), 7.33-7.27 (m, 1H), 6.89 (s, 1H), 5.17 (s, 2H), 4.36 (s, 2H), 4.09 (s, 2H), 3.96 (d, J = 8.6 Hz, 2H), 3.72 (br s, 1H), 3.63-3.57 (m, 1H), 3.32-3.21 (m, 1H), 3.04 (br s, 2H), 2.77 (br s, 2H), 2.11 (br s, 1H), 2.03 (br s, 1H), 1.65 (br s, 1H), 1.56 (br s, 1H), 1.41 (s, 9H); MS (CIAD ⁺ ) m/z 575.3 [M+H] ⁺ .

Example 137B: 5-[6-(benzyloxy)-8-fluoro-2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate

[00609] A vial containing a suspension of tert -butyl 4-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]piperidine-1-carboxylate (0.161 g, 0.280 mmol) in dichloromethane (0.93 mL) was cooled to 0 °C. 2,2,2-Trifluoroacetic acid (0.22 mL, 2.8 mmol) was then added dropwise, after which the cooling bath was removed. After 1 h, the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (2×1 mL) and then co-evaporated with methanol (1 mL) to give the title compound. This material was used without further purification. MS (APCI ⁺ ) m/z 475.3 [M+H] ⁺ .

Example 137C: 5-[6-(benzyloxy)-8-fluoro-2-{1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00610] To a vial containing 5-[6-(benzyloxy)-8-fluoro-2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, 2,2,2-trifluoroacetate (theoretical 0.280 mmol) were added 1,2-dichloroethane (1.4 mL) and triethylamine (0.078 mL, 0.56 mmol). The mixture was stirred for 10 min, then 1,3,5-trimethyl-1 H -pyrazole-4-carbaldehyde (0.058 g, 0.42 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.148 g, 0.700 mmol) was added. After 18 hours, additional 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (0.058 g, 0.42 mmol) was added, followed after 15 minutes by additional sodium triacetoxyhydroborate (0.148 g, 0.700 mmol). After twenty-four hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) using dichloromethane. The resulting biphasic mixture was stirred for 20 minutes. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.120 g, 0.201 mmol, 72% yield over two steps). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.47-7.42 (m, 2H), 7.36-7.30 (m, 2H), 7.30-7.23 (m, 1H), 6.71 (s, 1H), 5.07 (s, 2H), 3.99 (s, 2H), 3.94 (br s, 2H), 3.61 (s, 3H), 3.59 (br s, 2H), 3.35 (br s, 2H), 2.85 (br s, 2H), 2.73 (br s, 5H), 2.20 (s, 3H), 2.12 (s, 3H), 2.05-1.94 (br m, 2H), 1.79-1.60 (br m, 2H); MS (CIAD ⁺ ) m/z 597.4 [M+H] ⁺ .

Example 137D: 5-(8-fluoro-6-hydroxy-2-{1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00611] A vial containing a suspension of 5-[6-(benzyloxy)-8-fluoro-2-{1-[(1,3,5-trimethyl- 1H- pyrazol-4-yl)methyl]piperidin-4-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.110 g, 0.184 mmol) and 1,2,3,4,5-pentamethylbenzene (0.082 g, 0.55 mmol) in dichloromethane (1.8 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.5 mL, 1.5 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 60 min, the mixture was recooled to -78 °C, diluted with dichloromethane (3 mL) and quenched by successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g Biotage ^® Sfär C18 Duo 100 column 30 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.072 g, 0.14 mmol, 77% yield). ¹ H NMR (600 MHz, DMSO -d ₆ ) δ ppm. 9.18 (s, 1H), 8.86 (br s, 1H), 6.45 (s, 1H), 3.99 (br s, 2H), 3.93 (s, 2H), 3.65 (s, 3H), 3.60 (br s, 2H), 3.34 (br s, 2H), 3.17 (br s, 1H), 2.85 (br s, 2H), 2.81-2.64 (br m, 4H), 2.25 (s, 3H), 2.15 (s, 3H), 2.05-1.96 (br m, 2H), 1.77-1.67 (br m, 2H); MS (APCI ⁺ ) m/z 507.4 [M+H] ⁺ .

Example 138: 5-(8-fluoro-6-hydroxy-2-{2-[(1,3,5-trimethyl-1H - pyrazol-4-yl)methyl]-2-azaspiro[3.3]heptan-6-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 237)

Example 138A: tert-butyl 6-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-azaspiro[3.3]heptane-2-carboxylate

[00612] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate (Example 93A, theoretical 0.407 mmol) were added 1,2-dichloroethane (2.0 mL) and triethylamine (0.11 mL, 0.81 mmol). The mixture was stirred for 10 min, then tert-butyl 6-oxo-2-azaspiro[3,3]heptane-2-carboxylate (0.129 g, 0.611 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.216 g, 1.02 mmol) was added. After 12 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column Agela Claricep™ C18 100 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.220 g, 0.375 mmol, 92% yield over two steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.00 (br s, 1H), 7.52-7.46 (m, 2H), 7.39-7.32 (m, 2H), 7.32-7.26 (m, 1H), 6.90 (s, 1H), 5.16 (s, 2H), 4.37 (br s, 1H), 4.02 (br s, 1H), 3.99-3.94 (m, 2H), 3.90 (s, 2H), 3.81 (s, 2H), 3.74 (br s, 1H), 3.51 (br s, 1H), 3.13 (br s, 1H), 3.01 (s, 2H), 2.58 (br t, J = 8.9 Hz, 2H), 2.43 (br s, 2H), 1.37 (s, 9H); MS (APCI ⁺ ) m/z 587.3 [M+H] ⁺ .

Example 138B: 5-[2-(2-azaspiro[3.3]heptan-6-yl)-6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate

[00613] A vial containing a suspension of tert-butyl 6-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-azaspiro[3.3]heptane-2-carboxylate (0.082 g, 0.14 mmol) in dichloromethane (0.47 mL) was cooled to 0 °C. 2,2,2-Trifluoroacetic acid (0.11 mL, 1.4 mmol) was then added dropwise, after which the cooling bath was removed. After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (2×1 mL) and then co-evaporated with methanol (1 mL) to give the title compound. This material was used without further purification. MS (APCI ⁺ ) m/z 487.1 [M+H] ⁺ .

Example 138C: 5-[6-(benzyloxy)-8-fluoro-2-{2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-2-azaspiro[3.3]heptan-6-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00614] To a vial containing 5-[2-(2-azaspiro[3.3]heptan-6-yl)-6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, 2,2,2-trifluoroacetate (theoretical 0.14 mmol) were added 1,2-dichloroethane (0.70 mL) and triethylamine (0.039 mL, 0.28 mmol). The mixture was stirred for 10 min, then 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (0.029 g, 0.21 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.074 g, 0.35 mmol) was added. After 18 h, more 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (0.029 g, 0.21 mmol) was added, followed by more sodium triacetoxyhydroborate (0.074 g, 0.35 mmol) after 15 min. After 22 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) using dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.054 g, 0.089 mmol, 64% yield over two steps). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.49-7.43 (m, 2H), 7.36-7.30 (m, 2H), 7.30-7.24 (m, 1H), 6.71 (s, 1H), 5.07 (s, 2H), 4.00 (s, 2H), 3.97 (s, 2H), 3.95 (s, 2H), 3.83 (s, 2H), 3.60 (s, 3H), 3.30 (s, 2H), 2.80 (p, J =7.6 Hz, 1H), 2.71 (t, J =5.9 Hz, 2H), 2.46 (t, J =5.9 Hz, 2H), 2.42-2.36 (m, 2H), 2.21 (s, 3H), 2.11 (s, 3H), 2.09-2.03 (b/m, 2H); MS (CIAD ⁺ ) m/z 609.3 [M+H] ⁺ .

Example 138D: 5-(8-fluoro-6-hydroxy-2-{2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-2-azaspiro[3.3]heptan-6-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00615] A vial was charged with 5-[6-(benzyloxy)-8-fluoro-2-{2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-2-azaspiro[3.3]heptan-6-yl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.053 g, 0.088 mmol), ammonium formate (0.028 g, 0.44 mmol), and 10% palladium on carbon (0.009 g, 0.009 mmol). The vial was capped and purged with nitrogen. Ethanol (0.44 mL) was then added and the mixture was heated to 60°C. After 16 h, the mixture was cooled to ambient temperature and filtered through diatomaceous earth with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [column 120 g Biotage ^® Sfär C18 Duo 100 30 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.012 g, 0.023 mmol, 27% yield). ¹ H NMR (600 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 6.62 (s, 1H), 4.65 (d, J =15.3 Hz, 1H), 4.48 (d, J =15.2 Hz, 1H), 4.24 (s, 1H), 4.04-3.96 (m, 2H), 3.83-3.77 (m, 1H), 3.65 (dt, J =13.6, 7.4 Hz, 1H), 3.54 (s, 3H), 3.53-3.50 (m, 1H), 3.42-3.37 (m, 1H), 3.37 (s, 2H), 3.18-3.04 (m, 2H), 2.65 (s, 2H), 2.19 (t, J =10.0 Hz, 1H), 2.10 (s, 3H), 2.07-2.03 (m, 3H), 2.03 (s, 3H); MS (ESI ⁺ ) m/z 518.9 [M+H] ⁺ .

Example 139: 5-(2-{2-[1-(difluoromethyl)-3,5-dimethyl-1H - pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 238)

Example 139A: 5-[6-(benzyloxy)-2-{2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]ethyl}-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00616] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate (Example 93A, theoretical 0.15 mmol) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(1-(difluoromethyl)-3,5-dimethyl- 1H- pyrazol-4-yl)acetaldehyde (0.043 g, 0.23 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 16 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 ml) with dichloromethane. The resulting two-phase mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 25 ml). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [column 120 g Biotage ^® Sfär C18 Duo 100 30 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.040 g, 0.070 mmol, 46% yield over two steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 9.89 (br s, 1H), 7.67 (t, J = 58.2 Hz, 1H), 7.52-7.48 (m, 2H), 7.38-7.33 (m, 2H), 7.32-7.28 (m, 1H), 6.91 (s, 1H), 5.17 (s, 2H), 4.63 (br s, 1H), 4.25 (br s, 1H), 3.98 (s, 2H), 3.81 (br s, 1H), 3.32 (br s, 3H), 3.07 (s, 2H), 2.85 (t, J = 8.6 Hz, 2H), 2.36 (s, 3H), 2.19 (s, 3H); MS (CIAD ⁺ ) m/z 564.3 [M+H] ⁺ .

Example 139B: 5-(2-{2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00617] A vial containing a suspension of 5-[6-(benzyloxy)-2-{2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]ethyl}-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.038 g, 0.067 mmol) and 1,2,3,4,5-pentamethylbenzene (0.030 g, 0.20 mmol) in dichloromethane (0.67 mL) was cooled to -78 °C with stirring under nitrogen atmosphere. Trichloroborane (1.0 M in dichloromethane) (0.54 mL, 0.54 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 60 min, the mixture was recooled to -78 °C, diluted with dichloromethane (5 mL) and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.031 g, 0.065 mmol, 97% yield). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.57 (t, J = 58.2 Hz, 1H), 6.60 (s, 1H), 4.23 (br s, 2H), 3.99 (s, 2H), 3.23 (t, J = 8.5 Hz, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.83 (dd, J = 10.1, 7.0 Hz, 2H), 2.32 (s, 3H), 2.16 (s, 3H). Note: Two essential protons are not accounted for; MS (APCI ⁺ ) m/z 474.2 [M+H] ⁺ .

Example 139C: 2-(1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl)ethan-1-ol

[00618] To the vial were added 2-(3,5-dimethyl-1H-pyrazol-4-yl)ethan-1-ol (0.282 g, 2.01 mmol), potassium fluoride (0.234 g, 4.03 mmol), and acetonitrile (8.1 mL). The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere. A solution of diethyl (bromodifluoromethyl)phosphonate (0.538 g, 2.01 mmol) in acetonitrile (2.0 mL) was then added dropwise. The resulting mixture was stirred at ambient temperature. After 20 h, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by silica gel chromatography [12 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound (0.377 g, 1.98 mmol, 98% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 7.09 (t, J = 59.3 Hz, 1H), 3.69 (td, J = 6.7, 5.6 Hz, 2H), 2.62 (t, J = 6.7 Hz, 2H), 2.36 (s, 3H), 2.20 (t, J = 1.1 Hz, 3H), 1.53 (t, J = 5.7 Hz, 1H); MS (APCI ⁾ m/z 191.7 [M+H] ⁺ .

Example 139D: 2-(1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetaldehyde

[00619] To the flask were added 2-(1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl)ethan-1-ol (0.360 g, 1.89 mmol) and dichloromethane (9.5 mL). The suspension was stirred at ambient temperature and Dess-Martin periodinane (1.20 g, 2.84 mmol) was added portionwise. After 2 h, the solids were removed by filtration through diatomaceous earth with tert-butyl methyl ether. The filtrate was concentrated under reduced pressure. The residue was treated with tert-butyl methyl ether (50 mL) and stirred with 0.1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1 v/v) (50 mL) for 15 min. The layers were then separated and the aqueous phase was extracted with tert -butyl ether (3 x 20 mL). The organic phases were combined, washed with brine, dried over magnesium sulfate/sodium sulfate (1:1 by weight) and concentrated under reduced pressure to give the title compound (0.348 g, 1.85 mmol, 98% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.62 (t, J = 2.0 Hz, 1H), 7.12 (t, J = 59.3 Hz, 1H), 3.44 (d, J = 2.1 Hz, 2H), 2.34 (s, 3H), 2.16 (s, 3H); MS (APCI ⁺ ) m/z 189.7 [M+H] ⁺ .

Example 140: 5-{2-[2-(bicyclo[2.2.1]heptan-1-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 239)

Example 140A: 2-(bicyclo[2.2.1]heptan-1-yl)acetaldehyde

[00620] Dess-Martin periodinane (275 mg, 0.648 mmol, 1.0 equivalent) was added to a solution of 2-(bicyclo[2.2.1]heptan-1-yl)ethanol (91 mg, 0.648 mmol, 1 equivalent) in dichloromethane (3.3 mL) at 23 °C. The reaction mixture was stirred for 1.5 h at 23 °C. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate (5 mL), saturated aqueous sodium thiosulfate (5 mL), ether (25 mL), and pentane (3 mL). The organic layer was washed with saturated aqueous sodium chloride (3 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The resulting residue was suspended in ether (3 mL) and the suspension was filtered through a pad of diatomaceous earth (1.0 cm × 0.5 cm). The filter cake was washed with ether (3 × 1.0 mL). The filtrates were combined and concentrated. The resulting title compound was used without further purification in the next step.

Example 140B: 5-{6-(benzyloxy)-2-[2-(bicyclo[2.2.1]heptan-1-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00621] Sodium triacetoxyborohydride (97 mg, 0.46 mmol, 1.2 equivalents) was added in one portion to a suspension of the product of Example 140A (nominally 0.648 mmol, 2.0 equivalents), triethylamine (0.14 mL, 0.972 mmol, 3.0 equivalents), and 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominally 0.324 mmol, 1 equivalent, Example 54A) in acetonitrile (0.75 mL) at 23°C. The reaction mixture was stirred for 18 hours at 23°C. The reaction mixture was then diluted with saturated aqueous ammonium chloride (0.5 mL), water (0.5 mL), and dimethyl sulfoxide (2.0 mL). The diluted mixture was purified by reverse-phase flash column chromatography (50 g RediSep Rf ^Gold® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (45 mg, 0.085 mmol, 27% yield). MS ( ^APCI ) m/z 514 [M+H] ⁺ .

Example 140C: 5-{2-[2-(bicyclo[2.2.1]heptan-1-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00622] A suspension of palladium on carbon (10 wt %, 9.3 mg, 0.009 mmol, 10.0 mol %), ammonium formate (28 mg, 0.438 mmol, 5.0 equivalents), and the product of Example 140B (45 mg, 0.088 mmol, 1 equivalent) in ethanol (0.5 mL) was sealed in a beaker with a screw cap to release the pressure. The sealed vessel was placed in a heating block preheated to 50 °C. The reaction mixture was stirred for 1 h at 50 °C. The reaction mixture was then cooled to 23 °C. The cooled mixture was filtered through a pad of diatomaceous earth (1.0 cm × 0.5 cm). The filter cake was washed with methanol (3 × 1.0 mL). The filtrates were combined and concentrated. The resulting residue was purified by reverse phase flash column chromatography (5.5 g RediSep Rf Gold ^® C18 column, eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 13 mL/min) to give the title compound (22 mg, 0.05 mmol, 57% yield). 1H NMR (500 MHz, DMSO -d 6) δ ppm. 9.65 (lat, 1H), 6.57 (s, 1H), 4.60-4.06 (m, 1H), 3.94 (s, 2H), 3.79-3.49 (m, 1H)*, 3.23 (aps, 2H), 2.97 (aps, lat), 2.16 (s, 1H), 2.14-1.88 (m, 2H), 1.66-1.54 (m, 2H), 1.43-1.32 (m, 2H), 1.32-1.20 (m, 4H), 1.17 (s, 2H); MS (CIAD ⁺ ) m/z 424 [M+H] ⁺ .

Example 141: 5-[7-amino-1-fluoro-3-hydroxy-7-(prop-2-en-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 240)

Example 141A: N ' -[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydronaphthalen-2(1H)-ylidene]benzohydrazide

[00623] To a suspension of the product of Example 67F (1.0207 g, 2.52 mmol) in ethanol (20 mL) was added benzohydrazide (0.412 g, 3.03 mmol), and the resulting suspension was vigorously stirred. After 20 min, the mixture was diluted with water (40 mL), sonicated for 1 min, and vigorously stirred for 5 min. The resulting solid was collected by filtration, washed with water (3 x 10 mL), and dried in a vacuum oven at 50 °C to give the title compound (1.1295 g, 2.162 mmol, 86% yield). ¹ H NMR showed a mixture of E/Z isomers and rotamers. MS (APCI ⁺ ) m/z 523 [M+H] ⁺ .

Example 141B: N ' -[6-(benzyloxy)-8-fluoro-2-(prop-2-en-1-yl)-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]benzohydrazide

[00624] To a solution of allyltrichlorosilane (1 mL, 6.90 mmol) in 1,2-dichloroethane (20 mL) at 0 °C was added triethylamine (1.742 mL, 12.5 mmol), followed by the dropwise addition of 2-(methylamino)ethanol (0.5 mL, 6.25 mmol). After 30 min, the mixture was warmed to ambient temperature. After 20 h, the mixture was filtered through ^Celite® (1.5 g) and the solid was washed with 1,2-dichloroethane (3 mL). The filtrate was transferred to a 25 mL volumetric flask and diluted to a total volume of 25 mL, giving a theoretical concentration of 2-allyl-2-chloro-3-methyl-1,3,2-oxazasilolidine of 0.25 M.

[00625] To a suspension of the product of Example 141A (0.5623 g, 1.076 mmol) in 1,2-dichloroethane (11 mL) was added triethylamine (0.150 mL, 1.076 mmol). After 3 min, a solution of 2-allyl-2-chloro-3-methyl-1,3,2-oxazasilolidine (6.03 mL, 0.25 M in 1,2-dichloroethane, 1.507 mmol) was added and the resulting mixture was degassed with three additions of vacuum/nitrogen. After 18 h, the reaction was quenched with methanol (3 mL) and diluted with acetonitrile (11 mL). ^Celite® (3 g) was added and the mixture was concentrated in vacuo. The resulting residue was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to afford the title compound as an ammonium salt (0.1761 g, 0.388 mmol, 83.0% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.85 (s, 1H), 7.87-7.82 (m, 2H), 7.70-7.54 (m, 1H), 7.57-7.43 (m, 5H), 7.40-7.33 (m, 2H), 7.35-7.27 (m, 1H), 6.73 (s, 1H), 6.07 (ddt, J =16.4, 10.7, 7.3 Hz, 1H), 5.23 (s, 1H), 5.13-5.05 (m, 4H), 3.97 (d, J =2.7 Hz, 2H), 2.95 (dt, J =17.3, 6.6 Hz, 1H), 2.68 (d, J =7.2 Hz, 1H), 2.64 (s, 1H), 2.57 (s, 1H), 2.23 (d, J =7.3 Hz, 2H), 1.80 (dt, J =13.2, 6.5 Hz, 1H), 1.65 (dt, J =13.2, 6.4 Hz, 1H); MS (CIAD ⁺ ) m/z 565 [M+H] ⁺ .

Example 141C: 5-[7-amino-3-(benzyloxy)-1-fluoro-7-(prop-2-en-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00626] To a thoroughly degassed (5×vacuum/nitrogen backfill) solution of the product of Example 141B (0.200 g, 0.344 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (2 mL) was added a solution of samarium(II) iodide (10.32 mL, 0.1 M in tetrahydrofuran, 1.032 mmol) slowly over 3 min. After 20 min, the reaction mixture was diluted with water (2 mL) and acetonitrile (8 mL). ^Celite® (2 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.0770 g, 0.173 mmol, 50.3% yield). MS ( ^APCI ) m/z 446 [M+H] ⁺ .

Example 141D: 5-[7-amino-1-fluoro-3-hydroxy-7-(prop-2-en-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ 6,2,5-thiadiazolidine-1,1,3-trione

[00627] To a suspension of the product of Example 141C (0.0770 g, 0.173 mmol) and pentamethylbenzene (0.051 g, 0.346 mmol) in dichloromethane (3 mL) at -78 °C was added a solution of boron trichloride (2.074 mL, 1 M in dichloromethane, 2.074 mmol) slowly along the wall of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (1 mL) and then ethanol (1 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 3 mL), 1:1 ethyl acetate/heptanes (2 x 3 mL), dichloromethane (2 x 3 mL), and acetonitrile (2 x 3 mL) to give a solid that was dissolved in 1:1 dimethyl sulfoxide/methanol (6 mL). The resulting solution was filtered through a 0.45 μm PTFE frit, loaded directly onto a Teledyne ISCO 100 g reversed-phase C18 column, and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0238 g, 0.067 mmol, 38.7% yield). ¹ H NMR (600 MHz, DMSO _-d6 ) δ ppm 9.27 (s, 1H), 7.85 (s, 3H), 6.50 (s, 1H), 5.91 (ddt, J =17.5, 10.2, 7.4 Hz, 1H), 5.27-5.19 (m, 2H), 3.95 (d, J =13.1 Hz, 1H), 3.92 (d, J =13.1 Hz, 1H), 2.82-2.70 (m, 3H), 2.67 (d, J =16.8 Hz, 1H), 2.40-2.36 (m, 2H), 1.84 (hept, J =6.6 Hz, 2H); MS (CIAD ⁺ ) m/z 356 [M+H] ⁺ .

Example 142: N ' -[8-fluoro-6-hydroxy-2-propyl-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]benzohydrazide (Compound 241)

[00628] A suspension of the product of Example 141B (0.200 g, 0.344 mmol) and 10% palladium hydroxide on carbon (0.4 g, 46.6 wt % in water, 1.752 mmol) in a mixture of tetrahydrofuran (1.786 mL) and methanol (4.47 mL) was stirred for 16 h under 60 psi of hydrogen pressure. After filtration, ^Celite® (2 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 100 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to afford the title compound as the ammonium salt (0.0700 g, 0.142 mmol, 41.2% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.78 (s, 1H), 9.02 (s, 1H), 7.85-7.80 (m, 2H), 7.58-7.51 (m, 1H), 7.48 (dd, J =8.2, 6.7 Hz, 2H), 7.29-6.94 (m, 4H), 6.46 (s, 1H), 5.18 (s, 1H), 3.95 (s, 2H), 2.88 (dt, J = 17.5, 6.2 Hz, 1H), 2.64-2.54 (m, 2H), 2.54-2.44 (m, 1H), 1.78-1.71 (m, 1H), 1.69-1.62 (m, 1H), 1.51-1.41 (m, 2H), 1.44-1.32 (m, 2H), 0.86 (t, J =6.9 Hz, 3H); MS (CIAD ⁺ ) m/z 477 [M+H] ⁺ .

Example 143: 5-[8-fluoro-6-hydroxy-2-(3-hydroxybutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 242)

Example 143A: 5-{6-(benzyloxy)-2-[3-(benzyloxy)butyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00629] Triethylamine (0.055 mL, 0.396 mmol) was added to a vial containing a suspension of the product of Example 65A (100 mg, 0.198 mmol) in dichloromethane (1 mL) and the mixture was stirred at ambient temperature for 5 min. 3-(benzyloxy)butanal (35.3 mg, 0.198 mmol) in dichloromethane (1 mL) was then added and the mixture was allowed to stir for an additional 10 min. Sodium triacetoxyhydroborate (105 mg, 0.495 mmol) was then added and the reaction mixture was stirred at ambient temperature for 14 h. The reaction mixture was then stirred with saturated sodium bicarbonate (20 mL) for 20 min. The mixture was extracted with dichloromethane. The organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Agela Technologies Claricep™ Flash C18 100 column) 40-60 μm, 120 g, flow rate 50 mL/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO ₂ (s)]) to give the title compound (44.9 mg, 0.081 mmol, 41.0% yield). MS (APCI ⁺ ) m/z 554 [M+H] ⁺ .

Example 143B: 5-[8-fluoro-6-hydroxy-2-(3-hydroxybutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00630] Trichloroborane (1.0 M in dichloromethane, 539 μL, 0.539 mmol) was added to a vial containing a suspension of the product of Example 143A (37.3 mg, 0.067 mmol) and 1,2,3,4,5-pentamethylbenzene (30.0 mg, 0.202 mmol) in dichloromethane (674 μL) cooled to -78 °C. The mixture was stirred at -78 °C for 10 min and then at 0 °C for 20 min. The reaction mixture was again cooled to -78 °C and quenched by the sequential addition of ethyl acetate (2 mL) and ethanol (2 mL). The mixture was warmed to ambient temperature and stirred for an additional 15 min. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH ₇ with _CO2 (s)]) to give the title compound (14.3 mg, 0.038 mmol, 56.8% yield). ¹ H NMR (500 MHz, DMSO- d6 ) δ ppm 9.62 (s, 1H), 6.56 (s, 1H), 4.17 (s, 2H), 3.94 (s, 2H), 3.71 (ddd, J =8.1, 6.1, 3.9 Hz, 1H), 3.24-3.09 (m, 2H), 2.97 (d, J =6.2 Hz, 2H), 1.80 (td, J =11.7, 9.9, 4.9 Hz, 1H), 1.72 (dddd, J =13.2, 10.1, 8.1, 5.6 Hz, 1H), 1.46 (s, 2H), 1.12 (d, J =6.2 Hz, 3H); MS (CIAD ⁺ ) m/z 374 [M+H] ⁺ .

Example 144: 5-(8-fluoro-6-hydroxy-2-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 243)

Example 144A: 2-(1-(trifluoromethyl)cyclopropyl)acetaldehyde

[00631] 2-(1-(Trifluoromethyl)cyclopropyl)ethanol (106.2 mg, 0.689 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Pyridinium chlorochromate (297 mg, 1.378 mmol) was then added. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was filtered through a silica pad washed with dichloromethane. The filtrate was concentrated under reduced pressure to give the title compound (105 mg, 0.689 mmol, 63% yield), which was used without further purification. ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 9.88-9.75 (m, 1H), 2.55 (d, , J =2.4 Hz, 2H), 1.19-1.16 (m, 2H), 0.83-0.74 (m, 2H).

Example 144B: 5-[6-(benzyloxy)-8-fluoro-2-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00632] Triethylamine was added to a vial containing a suspension of Example 65A (110 mg, 0.218 mmol) in dichloromethane (1 mL) and stirred at ambient temperature for 5 minutes. Example 144A (51.5 mg, 0.339 mmol) dissolved in dichloromethane (1 mL) was then added and stirred at ambient temperature for 10 minutes. Sodium triacetoxyhydroborate (115 mg, 0.544 mmol) was then added and the reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with methanol (10 mL) and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (120 g Agela Technologies Claricep™ Flash C18 100 40-60 μm, flow rate 50 ml/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO ₂ (s)]) to give the title compound (78.3 mg, 0.040 mmol, 68.2% yield). MS (APCI ⁺ ) m/z 528 [M+H] ⁺ .

Example 144C: 5-(8-fluoro-6-hydroxy-2-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00633] Trichloroborane (1.0 M in dichloromethane, 1.190 mL, 1.187 mmol) was added to a vial containing a suspension of the product of Example 144B (78.3 mg, 0.148 mmol) and 1,2,3,4,5-pentamethylbenzene (66 mg, 0.445 mmol) in dichloromethane (1.48 mL) cooled to -78 °C. The mixture was stirred at -78 °C for 10 min and then at 0 °C for 20 min. The mixture was again cooled to -78 °C and quenched by the sequential addition of ethyl acetate (2 mL) and ethanol (2 mL). The mixture was then warmed to ambient temperature and stirred for an additional 15 min. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with _CO2 (s)]) to give the title compound (33.6 mg, 0.077 mmol, 51.8% yield ₎ . ¹ H NMR (500 MHz, DMSO- d6 / _D2O ) δ ppm. 6.58 (s, 1H), 4.30-4.07 (m, 2H), 3.99 (s, 2H), 3.30 (s, 4H), 3.02-2.91 (m, 2H), 2.06-1.96 (m, 2H), 0.98-0.95 (m, 2H), 0.85-0.82 (m, 2H); MS (APCI ⁺ ) m/z 438 [M+H] ⁺ .

Example 145: 5-[8-fluoro-6-hydroxy-2-(3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 244)

Example 145A: 5-[6-(benzyloxy)-8-fluoro-2-{3-[(propan-2-yl)oxy]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00634] To a vial containing a suspension of the product of Example 65A in acetonitrile (2 mL) (125 mg, 0.247 mmol) were added potassium carbonate (171 mg, 1.237 mmol) and 3-isopropoxypropyl methanesulfonate (87 mg, 0.445 mmol). The mixture was stirred at 60 °C for 6 hours. The reaction mixture was filtered through a pad of diatomaceous earth with acetonitrile and methanol, and the filtrate was concentrated under reduced pressure. The product was purified by reversed-phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 50 mL/min flow rate, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with _CO2 (s)]) to afford the title compound (91.7 mg, 0.187 mmol, 75% yield). MS ( ^APCI ) m/z 492 [M+H] ⁺ .

Example 145B: 5-[8-fluoro-6-hydroxy-2-(3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00635] Trichloroborane (1.0 M in dichloromethane, 1492 μL, 1.492 mmol) was added to a vial containing a suspension of the product of Example 145A (91.7 mg, 0.187 mmol) and 1,2,3,4,5-pentamethylbenzene (83 mg, 0.560 mmol) in dichloromethane (1865 μL) cooled to -78 °C. The mixture was stirred at -78 °C for 10 min and then at 0 °C for 1 h. The mixture was again cooled to -78 °C and quenched by the sequential addition of ethyl acetate (2 mL) and ethanol (2 mL). The mixture was then warmed to ambient temperature and stirred for an additional 15 min. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, flow rate 50 mL/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with CO ₂ (s)]) to give the title compound (28.1 mg, 0.078 mmol, yield 41.9%). ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ ppm. 6.60 (s, 1H), 4.43-4.05 (m, 3H), 3.96 (s, 2H), 3.51 (t, J =5.9 Hz, 2H), 3.27 (s, 2H), 3.01 (s, 2H), 1.89 (p, J =6.3 Hz, 2H); MS (CIAD ⁺ ) m/z 360 [M+H] ⁺ .

Example 146: 5-{2-[(2 S )-2-aminopropyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 2245)

Example 146A: tert-Butyl {(2S)-1-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]propan-2-yl}carbamate

[00636] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate (Example 93A, theoretical 0.305 mmol) were added potassium carbonate (0.211 g, 1.53 mmol), tert- butyl ( S )-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.109 g, 0.458 mmol), acetonitrile (0.57 mL), and water (0.19 mL). The vial was capped and the mixture was heated to 60°C. After 16 h, the reaction mixture was cooled to ambient temperature and treated with 1.0 M hydrochloric acid (6.1 mL, 6.1 mmol). The resulting mixture was stirred for 27 h at ambient temperature. After this time, water (30 mL) was added and the mixture was extracted with ethyl acetate (4 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. This material was used without further purification. MS (ESI ^- ) m/z 547.1 [MH] ^- .

Example 146B: 5-{2-[(2S)-2-aminopropyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00637] A flask containing a suspension of tert-butyl {(2S)-1-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]propan-2-yl}carbamate (theoretical 0.305 mmol) and 1,2,3,4,5-pentamethylbenzene (0.136 g, 0.915 mmol) in dichloromethane (3.1 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (3.1 mL, 3.1 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min, then the dry ice-acetone bath was removed and the mixture was allowed to warm to ambient temperature. After 3 h, the mixture was recooled to -78 °C, diluted with dichloromethane (3 mL), and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.044 g, 0.12 mmol, 40% yield over three steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 6.46 (s, 1H), 4.01-3.88 (m, 2H), 3.61 (d, J =14.7 Hz, 1H), 3.47-3.39 (m, 2H), 2.80-2.69 (m, 3H), 2.64-2.59 (m, 1H), 2.58-2.52 (m, 1H), 2.52-2.47 (m, 1H), 1.15 (d, J =6.5 Hz, 3H); MS (ESI ⁺ ) m/z 359.0 [M+H] ⁺ .

Example 147: 5-{2-[(2 R )-2-aminopropyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 246)

Example 147A: tert - butyl {(2R)-1-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]propan-2-yl}carbamate

[00638] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate (Example 93A, theoretical 0.305 mmol) were added potassium carbonate (0.211 g, 1.53 mmol), tert -butyl ( R )-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.109 g, 0.458 mmol), acetonitrile (0.57 mL), and water (0.19 mL). The vial was capped and the mixture was heated to 60°C. After 16 h, the reaction mixture was cooled to ambient temperature and treated with 1.0 M hydrochloric acid (6.1 mL, 6.1 mmol). The resulting mixture was stirred for 27 h at ambient temperature. After this time, water (30 mL) was added and the mixture was extracted with ethyl acetate (4 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. This material was used without further purification. MS (ESI ^- ) m/z 547.1 [MH] ^- .

Example 147B: 5-{2-[(2R)-2-aminopropyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00639] A flask containing a suspension of tert-butyl {(2 R )-1-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]propan-2-yl}carbamate (theoretical 0.305 mmol) and 1,2,3,4,5-pentamethylbenzene (0.136 g, 0.915 mmol) in dichloromethane (3.1 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (3.1 mL, 3.1 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min, then the dry ice-acetone bath was removed and the mixture was allowed to warm to ambient temperature. After 3 h, the mixture was recooled to -78 °C, diluted with dichloromethane (3 mL), and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.036 g, 0.090 mmol, 30% yield over three steps) in approximately 90% purity as determined by ¹ H NMR analysis. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 6.48 (s, 1H), 4.03-3.93 (m, 2H), 3.60 (d, J =14.7 Hz, 1H), 3.47-3.38 (m, 2H), 2.80-2.68 (m, 3H), 2.63-2.57 (m, 1H), 2.57-2.53 (m, 1H), 2.53-2.47 (m, 1H), 1.16 (d, J =6.4 Hz, 3H); MS (ESI ⁺ ) m/z 359.1 [M+H] ⁺ .

Example 148: 5-{8-fluoro-6-hydroxy-2-[2-(piperazin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 247)

Example 148A: tert-butyl 4-{2-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}piperazine-1-carboxylate

[00640] To a vial containing a suspension of the product of Example 65A (150 mg, 0.297 mmol) in acetonitrile (2 mL) was added potassium carbonate (205 mg, 1.484 mmol) and the mixture was stirred at ambient temperature for 15 minutes. Tert -butyl 4-(2-bromoethyl)piperazine-1-carboxylate (131 mg, 0.445 mmol) was then added and the mixture was stirred at 50 °C for 34 hours. The solution was filtered through a pad of diatomaceous earth, eluting with excess acetonitrile, and the filtrate was concentrated under reduced pressure. The product was purified by reverse phase column chromatography (Agel Technologies Claricep™ Flash C18 100 column) 40-60 μm, 120 g, flow rate 50 ml/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO ₂ (s)]) to give the title compound (45.4 mg, 0.075 mmol, 25.3% yield). MS (APCI ⁺ ) m/z 604 [M+H] ⁺ .

Example 148B: 5-{8-fluoro-6-hydroxy-2-[2-(piperazin-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00641] Trichloroborane (1.0 M in dichloromethane, 464 μL, 0.464 mmol) was added to a vial containing a suspension of the product of Example 148A (35 mg, 0.058 mmol) and 1,2,3,4,5-pentamethylbenzene (25.8 mg, 0.174 mmol) in dichloromethane (580 μL) cooled to -78 °C. The mixture was stirred at -78 °C for 10 min and then at 0 °C for 10 min. The mixture was cooled again to -78 °C, diluted with dichloromethane (2 mL), and quenched with ethanol (3 mL). The mixture was then stirred at ambient temperature for 15 min. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, flow rate 50 mL/min, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with _CO2 (s)]) to give the title compound (14.6 mg, 0.035 mmol, yield 60.9% ₎ . ¹ H NMR (500 MHz, DMSO- d6 ) δ ppm. 9.12 (s, 1H), 6.44 (s, 1H), 3.93 (s, 2H), 3.46 (s, 2H), 3.01 (t, J =5.1 Hz, 4H), 2.70 (t, J =5.8 Hz, 2H), 2.61 (dt, J =14.5, 8.3 Hz, 9H), 2.57 (s, 1H); MS (CIAD ⁺ ) m/z 414 [M+H] ⁺ .

Example 149: 5-(8-fluoro-6-hydroxy-2-{[ rac -(1 R ,2 R )-2-(pyridin-4-yl)cyclopropyl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 248)

Example 149A: 5-[6-(benzyloxy)-8-fluoro-2-{[rac-(1R,2R)-2-(pyridin-4-yl)cyclopropyl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00642] Sodium triacetoxyborohydride (64 mg, 0.30 mmol, 1.2 equivalents) was added to a suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione trifluoroacetate (nominally 0.25 mmol, 1 equivalent, Example 54A), triethylamine (0.11 mL, 0.80 mmol, 3.2 equivalents), and rac-(1R,2R) -2-(pyridin-4-yl)cyclopropane-1-carbaldehyde (44 mg, 0.30 mmol, 1.2 equivalents) in acetonitrile (1.2 mL) at 23°C. The reaction mixture was stirred for 18 h at 23°C. A solution of rac- (1 R ,2 R )-2-(pyridin-4-yl)cyclopropane-1-carbaldehyde (150 mg, 1.02 mmol, 4.1 equivalents) in acetonitrile (0.5 mL) was added at 23°C. The reaction mixture was stirred for 5 h at 23°C. The reaction mixture was successively diluted with saturated aqueous ammonium chloride (0.5 mL) and dimethyl sulfoxide (3.0 mL). The diluted mixture was purified by reverse phase flash column chromatography (100 g RediSep Rf Gold ^® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to afford the title compound (84 mg, 0.16 mmol, 64% yield). MS (APCI ⁺ ) m/z 523 [M+H] ⁺ .

Example 149B: 5-(8-fluoro-6-hydroxy-2-{[rac-(1R,2R)-2-(pyridin-4-yl)cyclopropyl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00643] A mixture of palladium on carbon (10 wt %, 34 mg, 0.03 mmol, 20 mol %), ammonium formate (51 mg, 0.80 mmol, 5.0 equivalents) and 5-[6-(benzyloxy)-8-fluoro-2-{[ rac -(1 S ,2 S )-2-(pyridin-4-yl)cyclopropyl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt (84 mg, 0.16 mmol, 1 equivalent) in ethanol (1.6 mL) was stirred for 20 h at 23°C. The reaction mixture was then filtered through a pad of diatomaceous earth (1.0 cm × 0.5 cm). The filter cake was washed with methanol (3 × 1.0 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue was purified by reverse-phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 40 mL/min) to afford the title compound (35 mg, 0.078 mmol, 48% yield). ¹ H NMR (400 MHz, DMSO- d 6) δ ppm 9.60 (br s, 1H), 8.38 (d, J =5.2 Hz, 2H), 7.15-7.12 (m, 2H), 6.52 (s, 1H), 4.25-4.02 (m, 2H), ~3.22-3.15 (m, 2H)*, 3.90 (s, 2H), 2.93 (lat s, 2H), 2.00 (dt, J =8.9, 4.9 Hz, 1H), 1.63-1.56 (m, 1H), 1.20 (dt, J =8.5, 5.1 Hz, 1H), 1.15 (dt, J =8.7, 5.3 Hz, 1H); *resonance is hidden by solvent. MS (APCI ⁺ ) m/z 433 [M+H] ⁺ .

Example 150: 5-[2-(2-cyclopentyl-2-methoxyethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 249)

Example 150A: 5-[6-(benzyloxy)-2-(2-cyclopentyl-2-methoxyethyl)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00644] Sodium triacetoxyborohydride (79 mg, 0.38 mmol, 1.5 equivalents) was added to a suspension of 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione trifluoroacetate (nominally 0.25 mmol, 1 equivalent, Example 54A), triethylamine (0.14 mL, 1.00 mmol, 4.0 equivalents), and 2-cyclopentyl-2-methoxyacetaldehyde (54 mg, 0.38 mmol, 1.5 equivalents) in acetonitrile (1.2 mL) at 23 °C. The reaction mixture was stirred for 3 h at 23 °C. The reaction mixture was successively diluted with saturated aqueous ammonium chloride (0.5 mL) and dimethyl sulfoxide (3.0 mL). The diluted mixture was purified by reverse-phase flash column chromatography (100 g RediSep Rf Gold ^® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to give the title compound (101 mg, 0.19 mmol, 78% yield). MS ( ^APCI ) m/z 518 [M+H] ⁺ .

Example 150B: 5-[2-(2-cyclopentyl-2-methoxyethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione, ammonium salt

[00645] A solution of boron trichloride in dichloromethane (1.0 M, 2.0 mL, 2.00 mmol, 10.3 equivalents) was added to a suspension of the product of Example 150A (101 mg, 0.195 mmol, 1 equivalent) and pentamethylbenzene (38 mg, 0.256 mmol, 1.3 equivalents) in dichloromethane (1.0 mL) at -78 °C. The reaction vessel was immediately transferred to a cooling bath at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C. The reaction vessel was then transferred to a cooling bath at -78 °C and cooled to -78 °C over 15 min. A solution of boron tribromide in dichloromethane (0.2 mL, 0.20 mmol, 1.0 equivalent) was added at -78 °C. The reaction vessel was immediately transferred to a cooling bath at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. Then the reaction vessel was transferred to a cooling bath at -78 °C and cooled over 15 min to -78 °C. The reaction mixture was slowly diluted with ethanol (1.0 mL) at -78 °C. The diluted mixture was heated over 15 min to 23 °C. The heated mixture was concentrated. The resulting residue was purified by reverse-phase flash column chromatography (50 g RediSep Rf ^Gold® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 40 ml/min). Fractions containing the product were collected and concentrated. The resulting residue was re-purified by reverse-phase flash column chromatography (5.5 g RediSep Rf Gold ^® C18 column, eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 13 mL/min) to give the title compound (9 mg, 0.020 mmol, 10% yield). 1H NMR (400 MHz, DMSO- d 6) δ ppm. 9.62 (br, 1H), 7.26-6.93 (m, 1H), 6.54 (s, 1H), 3.94 (s, 2H), 3.37 (s, 3H), 3.09-2.75 (m, 2H), 2.19-2.03 (m, 1H), 1.79-1.17 (m, 8H); MS (APCI ⁺ ) m/z 428 [M+H] ⁺ .

Example 151: 5-{2-[(2 R )-2-amino-4-cyclohexylbutanoyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 250)

Example 151A: (9H-fluoren-9-yl)methyl {(2R)-1-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]-4-cyclohexyl-1-oxobutan-2-yl}carbamate, ammonium salt

[00646] N,N -diisopropylethylamine (0.30 mL, 1.73 mmol, 6.9 equivalents) was added to a suspension of 2-(1 H -benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 88 mg, 0.28 mmol, 1.1 equivalents), ( R )-α-[[(9 H -fluoren-9-ylmethoxy)carbonyl]amino]cyclohexanebutanoic acid (153 mg, 0.38 mmol, 1.5 equivalents), and 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetate (nominal 0.25 mmol, 1 equivalent, Example 54A) in acetonitrile (1.2 mL) at 23 °C. The reaction mixture was stirred for 18 h at 23 °C. The reaction mixture was diluted with water (0.5 mL) and dimethyl sulfoxide (1.0 mL). The diluted mixture was purified by reverse phase flash column chromatography (100 g RediSep Rf ^Gold® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 60 mL/min). The fractions containing the product were collected and concentrated. The resulting title compound was used without further purification in the next step. MS (APCI ⁺ ) m/z 781 [M+H] ⁺ .

Example 151B: 5-{2-[(2R)-2-amino-4-cyclohexylbutanoyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

A mixture of palladium on carbon (10 wt %, 53 mg, 0.05 mmol, 10 mol %), ammonium formate (79 mg, 1.25 mmol, 5.0 equivalents), and the product of Example 151A (nominally 0.25 mmol, 1 equivalent) in ethanol (1.3 mL) was stirred for 1.5 h at 50 °C. The reaction mixture was then cooled to 23 °C. The cooled mixture was filtered through a pad of diatomaceous earth (1.0 cm × 0.5 cm). The filter cake was washed with methanol (3 × 1.0 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue was purified by reverse phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column eluted with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratically eluted with 100% methanol in 3 column volumes, flow rate = 40 mL/min) to give the title compound (35 mg, 0.072 mmol, 30% over three steps). 1H NMR (400 MHz, DMSO- d 6) δ ppm. 6.58 (s, 1H), 4.73-4.26 (m, 1H), 3.96 (s, 2H), 3.81-3.63 (m, 2H), 1.83-1.53 (m, 7H), 1.36-1.08 (m, 6H), 0.97-0.80 (m, 2H); MS (APCI ⁺ ) m/z 469 [M+H] ⁺ .

Example 152: 5-(8-fluoro-6-hydroxy-2-{3-[(propan-2-yl)oxy]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 251)

[00647] The product of Example 145A (50.4 mg, 0.103 mmol) in tetrahydrofuran (4 mL) was added to 5% Pd/C, wet (50 mg, 0.219 mmol) in a 20 mL Barnstead STEM RS10 reactor and the mixture was stirred at 25 °C under 57-65 psi hydrogen for 21.5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The product was purified by reversed-phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10 to 100% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with _CO2 (s)]) to afford the title compound (32.3 mg, 0.080 mmol, 78% yield). ¹ H NMR (600 MHz, DMSO _-d6 ) δ ppm 9.64 (s, 1H), 6.57 (s, 1H), 4.14 (s, 1H), 3.94 (s, 2H), 3.55 (p, J =6.1 Hz, 1H), 3.44 (t, J =5.9 Hz, 2H), 3.23 (s, 5H), 2.98 (s, 2H), 1.93 (s, 2H), 1.09 (d, J =6.1 Hz, 6H); MS (CIAD ⁺ ) m/z 402 [M+H] ⁺ .

Example 153: 5-{8-fluoro-6-hydroxy-2-[2-(1-methyl-1 H -pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 252)

Example 153A: 5-{6-(benzyloxy)-8-fluoro-2-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00648] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate (Example 93A, theoretical 0.15 mmol) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(1-methyl- 1H- pyrazol-4-yl)acetaldehyde (0.028 g, 0.23 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 14 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 ml) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 25 ml). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.065 g, 0.13 mmol, 85% yield over two steps). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.58 (s, 1H), 7.47 (d, J = 7.4 Hz, 2H), 7.38-7.32 (m, 3H), 7.32-7.25 (m, 1H), 6.88 (s, 1H), 5.14 (s, 2H), 4.33 (br s, 2H), 3.99 (s, 2H), 3.77 (s, 3H), 3.48 (br s, 2H), 3.45-3.31 (m, 2H), 3.13-3.00 (m, 2H), 2.90 (t, J = 8.2 Hz, 2H); MS (APCI ⁺ ) m/z 500.3 [M+H] ⁺ .

Example 153B: 5-{8-fluoro-6-hydroxy-2-[2-(1-methyl-1H-pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00649] A vial containing a suspension of 5-{6-(benzyloxy)-8-fluoro-2-[2-(1-methyl- 1H- pyrazol-4-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.063 g, 0.13 mmol) and 1,2,3,4,5-pentamethylbenzene (0.056 g, 0.38 mmol) in dichloromethane (1.3 mL) was cooled to -78 °C with stirring under nitrogen atmosphere. Trichloroborane (1.0 M in dichloromethane) (1.0 mL, 1.0 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 60 min, the mixture was recooled to -78 °C, diluted with dichloromethane (3 mL) and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.046 g, 0.11 mmol, 89% yield). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.54 (s, 1H), 7.34 (s, 1H), 6.57 (s, 1H), 4.15 (br s, 2H), 3.98 (s, 2H), 3.75 (s, 3H), 3.26 (br s, 4H), 2.95 (s, 2H), 2.85 (t, J = 8.1 Hz, 2H); MS (ESI ⁺ ) m/z 410.1 [M+H] ⁺ .

Example 153C: 2-(1-methyl-1H-pyrazol-4-yl)acetaldehyde

[00650] 2-(1-methyl- 1H- pyrazol-4-yl)ethan-1-ol (0.200 g, 1.59 mmol) and dichloromethane (7.9 mL) were added to the vial. The suspension was stirred at ambient temperature and Dess-Martin periodinane (1.01 g, 2.38 mmol) was added portionwise. After 30 min, the solids were removed by filtration through diatomaceous earth using tert-butyl methyl ether/ethyl acetate (1:1 v/v). The filtrate was concentrated under reduced pressure. The residue was treated with tert-butyl methyl ether/ethyl acetate (1:1 v/v) (50 mL) and stirred with 0.1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1 v/v) (50 mL) for 15 min. The layers were then separated and the aqueous phase was extracted with tert -butyl methyl ether/ethyl acetate (1:1 v/v) (3 x 20 mL). The organic phases were combined, washed with brine, dried over magnesium sulfate/sodium sulfate (1:1 by weight) and concentrated under reduced pressure. The residue was filtered through a short pad of silica gel using heptanes/ethyl acetate (1:1 v/v) to give the title compound (0.077 g, 0.62 mmol, 39% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm. 9.71 (t, J =2.0 Hz, 1H), 7.39 (s, 1H), 7.33 (s, 1H), 3.90 (s, 3H), 3.57 (dt, J =1.9, 0.6 Hz, 2H).

Example 154: 5-(2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1H - pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 253)

Example 154A: 5-[6-(benzyloxy)-2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl]ethyl}-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00651] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate (Example 93A, theoretical 0.15 mmol) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(1-(2,2-difluoroethyl)-3,5-dimethyl- 1H- pyrazol-4-yl)acetaldehyde (0.046 g, 0.23 mmol) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 14 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 ml) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 25 ml). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.076 g, 0.13 mmol, 86% yield over two steps). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.51-7.44 (m, 2H), 7.38-7.32 (m, 2H), 7.32-7.24 (m, 1H), 6.89 (s, 1H), 6.22 (tt, J = 55.0, 3.8 Hz, 1H), 5.14 (s, 2H), 4.41 (td, J = 15.1, 3.8 Hz, 2H), 4.28 (br s, 2H), 3.99 (s, 2H), 3.35 (br s, 2H), 3.24-3.14 (m, 2H), 3.13-3.01 (m, 2H), 2.86-2.71 (m, 2H), 2.19 (s, 3H), 2.11 (s, 3H); MS (CIAD ⁺ ) m/z 578.3 [M+H] ⁺ .

Example 154B: 5-(2-(2-(1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl)ethyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide

[00652] A vial containing a suspension of 5-[6-(benzyloxy)-2-{2-[1-(2,2-difluoroethyl)-3,5-dimethyl- 1H- pyrazol-4-yl]ethyl}-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.074 g, 0.13 mmol) and 1,2,3,4,5-pentamethylbenzene (0.057 g, 0.38 mmol) in dichloromethane (1.3 mL) was cooled to -78 °C with stirring under nitrogen atmosphere. Trichloroborane (1.0 M in dichloromethane) (1.0 mL, 1.0 mmol) was then slowly added. The resulting brownish mixture was stirred at -78 °C for 10 min and then the dry ice-acetone bath was replaced with an ice water bath. After 60 min, the mixture was recooled to -78 °C, diluted with dichloromethane (3 mL) and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.053 g, 0.11 mmol, 86% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 9.84 (br s, 1H), 9.72 (s, 1H), 6.60 (s, 1H), 6.27 (tt, J = 55.1, 3.9 Hz, 1H), 4.57 (br s, 1H), 4.44 (td, J = 15.0, 3.9 Hz, 2H), 4.19 (br s, 1H), 3.96 (s, 2H), 3.81 (br s, 1H), 3.27 (br s, 1H), 3.17 (br s, 2H), 3.04 (s, 2H), 2.80 (t, J = 8.6 Hz, 2H), 2.21 (s, 3H), 2.13 (s, 3H); MS (ESI ⁺ ) m/z 487.6 [M+H] ⁺ .

Example 154C: 1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazole-4-carbaldehyde

[00653] To the vial were added 3,5-dimethyl- 1H -pyrazole-4-carbaldehyde (0.050 g, 0.40 mmol), potassium carbonate (0.111 g, 0.806 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (0.129 g, 0.604 mmol), and acetonitrile (1.0 mL). The vial was capped and the mixture was heated to 60 °C. After 18 h, the reaction mixture was cooled to ambient temperature and filtered through a thin pad of diatomaceous earth with dichloromethane. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography [4 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound (0.057 g, 0.31 mmol, 76% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 9.93 (s, 1H), 6.11 (tt, J = 55.4, 4.4 Hz, 1H), 4.34 (td, J = 13.2, 4.4 Hz, 2H), 2.54 (s, 3H), 2.44 (s, 3H); MS (APCI ⁺ ) m/z 230.6 [M+CH ₃ CN+H] ⁺ .

Example 154D: 1-(2,2-difluoroethyl)-4-(2-methoxyvinyl)-3,5-dimethyl-1H-pyrazole

[00654] (Methoxymethyl)triphenylphosphonium chloride (1.05 g, 3.07 mmol) and tetrahydrofuran (5.9 mL) were added to the flask. The flask was cooled to 0 °C, then potassium 2-methylpropan-2-olate (1.0 M in tetrahydrofuran) (2.8 mL, 2.8 mmol) was added. The white suspension immediately turned into a dark red suspension, which was stirred for 15 min. A solution of 1-(2,2-difluoroethyl)-3,5-dimethyl-1 H -pyrazole-4-carbaldehyde (0.445 g, 2.37 mmol) in tetrahydrofuran (5.9 mL) was then added. The resulting mixture was stirred at 0 °C for 2 h and then at ambient temperature for 5 h. The mixture was then poured into saturated aqueous ammonium chloride solution (80 mL) and extracted with ethyl acetate (4 x 25 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [24 g column, gradient 0-100% ethyl acetate in heptanes] to give 1-(2,2-difluoroethyl)-4-(2-methoxyvinyl)-3,5-dimethyl- 1H- pyrazole as a mixture of olefin isomers [69:31 ( E )-( Z )] (0.205 g, 0.948 mmol, 40% yield). Data for the ( E )-isomer: ¹ H NMR (500 MHz, _CDCl3 ) δ ppm. 6.57 (d, J = 13.0 Hz, 1H), 6.04 (tt, J = 55.9, 4.5 Hz, 1H), 5.48 (d, J = 13.1 Hz, 1H), 4.30 (td, J = 13.3, 4.6 Hz, 2H), 3.66 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H). Data for ( Z )-isomer: ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm. 6.06 (td, J =55.6, 4.6 Hz, 1H), 6.02 (d, J =6.7 Hz, 1H), 4.98 (d, J =6.7 Hz, 1H), 4.30 (td, J =13.3, 4.6 Hz, 2H), 3.67 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H); MS (CIAD ⁺ ) m/z 217.6 [M+H] ⁺ .

Example 154E: 2-(1-(2,2-difluoroethyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetaldehyde

[00655] To the vial were added 1-(2,2-difluoroethyl)-4-(2-methoxyvinyl)-3,5-dimethyl- 1H- pyrazole (0.170 g, 0.786 mmol) and tetrahydrofuran (2.6 mL). The vial was cooled to 0 °C. The solution was treated with 6.0 M hydrochloric acid (2.6 mL, 16 mmol) and then the ice bath was removed. The reaction mixture was allowed to warm to ambient temperature and then heated to 50 °C. After 16 h, the vial was cooled to ambient temperature and the solution was transferred to a beaker containing saturated aqueous sodium bicarbonate (60 mL). The resulting mixture was stirred for 15 min and then extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography [4 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound (0.135 g, 0.668 mmol, 85% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 9.59 (t, J = 2.3 Hz, 1H), 6.06 (tt, J = 55.7, 4.4 Hz, 1H), 4.32 (td, J = 13.4, 4.4 Hz, 2H), 3.42 (d, J = 2.3 Hz, 2H), 2.19 (s, 3H), 2.16 (s, 3H); MS (ESI ⁺ ) m/z 203.4 [M+H] ⁺ .

Example 155: 5-[7-amino-1-fluoro-3-hydroxy-7-(4-methylpentyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 254)

Example 155A: N ' -[6-(benzyloxy)-8-fluoro-2-[(2E)-4-methylpenta-2,4-dien-1-yl]-7-(1,1,4-trioxo-1λ6,2,5 ^- thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]benzohydrazide

[00656] To a solution of the product of Example 141B (0.5208 g, 0.895 mmol) and [(di(1-adamantyl)butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, (cataCXium® A Pd G3, 0.033 g, 0.045 mmol) in N,N -dimethylacetamide (5.2 mL) was added N,N -diisopropylethylamine (0.469 mL, 2.69 mmol) followed by 2-bromopropene (0.118 mL, 1.343 mmol). The resulting mixture was degassed with 5 additions of vacuum/nitrogen and then heated to 100 °C. After 24 h, the reaction mixture was cooled to ambient temperature and diluted with acetonitrile (20 mL). ^Celite® (10 g) was added and the mixture was concentrated to give a powder which was dry loaded onto a Teledyne ISCO 275 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in pH7 buffer to give the title compound as the ammonium salt (0.2766 g, 0.445 mmol, 49.7% yield) as a mixture of E and Z isomers. MS (APCI ⁺ ) m/z 605 [M+H] ⁺ .

Example 155B: N ' -[8-fluoro-6-hydroxy-2-(4-methylpentyl)-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]benzohydrazide

[00657] A suspension of the product of Example 155A (0.425 g, 0.684 mmol) and 10% palladium(II) hydroxide on carbon (0.230 g, 50 wt% in water, 0.820 mmol) in a mixture of methanol (8.54 mL) and tetrahydrofuran (2.85 mL) was stirred for 16 h under 60 psi of hydrogen. Filtration and concentration of the filtrate gave the title compound (0.2794 g, 0.539 mmol, 79% yield), which was used in the next reaction without purification. MS ( ^APCI ) m/z 519 [M+H] ⁺ .

Example 155C: 5-[7-amino-1-fluoro-3-hydroxy-7-(4-methylpentyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00658] To a thoroughly degassed solution (5×vacuum/nitrogen backfill) of the product of Example 155B (0.2990 g, 0.577 mmol) in methanol (6 mL) was slowly added a solution of samarium(II) iodide (17.3 mL, 0.1 M in tetrahydrofuran, 1.73 mmol). After 5 min, the reaction mixture was quenched with water (1.5 mL) and diluted with acetonitrile (15 mL). ^Celite® (3 g) was added and the resulting mixture was concentrated to give a powder which was dry loaded onto a Teledyne ISCO 100 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.097 g, 0.243 mmol, 42.1% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.29 (s, 1H), 8.17-7.57 (m, 3H), 6.51 (s, 1H), 4.00-3.90 (m, 2H), 2.81-2.72 (m, 3H), 2.68 (d, J = 16.5 Hz, 1H), 1.86 (t, J = 6.9 Hz, 2H), 1.60-1.49 (m, 3H), 1.43-1.32 (m, 2H), 1.16 (k, J =7.2 Hz, 2H), 0.88 (dd, J =6.6, 1.3 Hz, 6H); MS (CIAD ⁺ ) m/z 400 [M+H] ⁺ .

Example 156: 5-(7-amino-1-fluoro-3-hydroxy-7-propyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 255)

[00659] To a thoroughly degassed solution (5×vacuum/nitrogen backfill) of the product of Example 142 (0.0456 g, 0.096 mmol) in methanol (1 mL) was slowly added a solution of samarium(II) iodide (2.87 mL, 0.1 M in tetrahydrofuran, 0.287 mmol). After 10 min, the reaction mixture was quenched with water (0.25 mL) and diluted with acetonitrile (3 mL). ^Celite® (1 g) was added and the resulting mixture was concentrated to give a powder which was dry loaded onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 by adding dry ice) to give the title compound (0.0118 g, 0.033 mmol, 34.5% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 6.49 (s, 1H), 3.98-3.88 (m, 2H), 2.77-2.70 (m, 3H), 2.63 (d, J =16.7 Hz, 1H), 1.82 (t, J =6.8 Hz, 2H), 1.58-1.51 (m, 2H), 1.43-1.31 (m, 2H), 0.89 (t, J =7.2 Hz, 3H); MS (CIAD ⁺ ) m/z 358 [M+H] ⁺ .

Example 157: 5-{2-[2-(1,3-dimethyl-1H- pyrazol -4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 256)

Example 157A: 5-{6-(benzyloxy)-2-[2-(1,3-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00660] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.15 mmol, Example 93A) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(1,3-dimethyl- 1H- pyrazol-4-yl)acetaldehyde (0.032 g, 0.23 mmol, Example 157D) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 14 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 ml) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 25 ml). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.070 g, 0.14 mmol, 89% yield over two steps). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.49-7.46 (m, 2H), 7.46 (s, 1H), 7.37-7.32 (m, 2H), 7.32-7.26 (m, 1H), 6.89 (s, 1H), 5.14 (s, 2H), 4.32 (br. s, 2H), 3.99 (s, 2H), 3.68 (s, 3H), 3.33 (t, J =8.6 Hz, 2H), 3.06 (t, J =6.3 Hz, 2H), 2.83 (dd, J =9.1, 7.9 Hz, 2H), 2.11 (s, 3H); MS (ESI ⁺ ) m/z 513.9 [M+H] ⁺ .

Example 157B: 5-{2-[2-(1,3-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00661] A flask containing a suspension of 5-{6-(benzyloxy)-2-[2-(1,3-dimethyl- 1H- pyrazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.066 g, 0.13 mmol) and 1,2,3,4,5-pentamethylbenzene (0.057 g, 0.39 mmol) in dichloromethane (1.3 mL) was cooled to -78 °C with stirring under nitrogen atmosphere. Trichloroborane (1.0 M in dichloromethane) (1.0 mL, 1.0 mmol) was then added. The resulting mixture was stirred at -78°C for 10 min, then the dry ice-acetone bath was replaced with an ice-water bath. After 60 min, the mixture was recooled to -78°C, diluted with dichloromethane (3 mL), and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.043 g, 0.10 mmol, 79% yield). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.45 (s, 1H), 6.59 (s, 1H), 4.30 (br s, 2H), 3.98 (s, 2H), 3.68 (s, 3H), 3.53 (br s, 2H), 3.30 (t, J = 8.3 Hz, 2H), 3.07-2.96 (m, 2H), 2.82 (dd, J =9.6, 7.1 Hz, 2H), 2.10 (s, 3H); MS (ESI ⁺ ) m/z 423.8 [M+H] ⁺ .

Example 157C: 4-(2-methoxyvinyl)-1,3-dimethyl-1H-pyrazole

[00662] (Methoxymethyl)triphenylphosphonium chloride (1.62 g, 4.71 mmol) and tetrahydrofuran (6.0 mL) were added to the flask. The flask was cooled to 0 °C, then potassium 2-methylpropan-2-olate (1.0 M in tetrahydrofuran, 4.4 mL, 4.4 mmol) was added. Fifteen minutes later, a solution of 1,3-dimethyl-1 H -pyrazole-4-carbaldehyde (0.450 g, 3.62 mmol) in tetrahydrofuran (6.0 mL) was added. The resulting mixture was stirred at 0 °C for 2 hours and then at ambient temperature for 46 hours. The mixture was then poured into saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (4 x 25 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [24 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound as a mixture of olefin isomers [60:40 ( E )-( Z )] (0.387 g, 2.54 mmol, 70% yield). Data for the ( E )-isomer: ¹ H NMR (400 MHz, _CDCl3 ) δ ppm 7.16 (s, 1H), 6.69 (d, J = 13.0 Hz, 1H), 5.54 (d, J = 13.1 Hz, 1H), 3.78 (s, 3H), 3.63 (s, 3H), 2.23 (s, 3H). Data for ( Z )-isomer: ¹ H NMR (400 MHz, _CDCl3 ) δ ppm 7.65 (s, 1H), 6.01 (d, J =6.4 Hz, 1H), 5.12 (d, J =6.5 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2.22 (s, 3H); MS (ESI ⁺ ) m/z 153.3 [M+H] ⁺ .

Example 157D: 2-(1,3-dimethyl-1H-pyrazol-4-yl)acetaldehyde

[00663] 4-(2-methoxyvinyl)-1,3-dimethyl- 1H- pyrazole (0.200 g, 1.31 mmol) and tetrahydrofuran (6.6 mL) were added to the vial. The vial was cooled to 0 °C. The solution was treated with 6.0 M hydrochloric acid (6.6 mL, 39 mmol) and then the ice bath was removed. The vial was allowed to warm to ambient temperature and then heated to 50 °C. After 16 h, the vial was cooled to ambient temperature and the solution was transferred to a beaker containing saturated aqueous sodium bicarbonate (60 mL). The resulting mixture was stirred for 15 min and then extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography [24 g column, gradient 0-100% ethyl acetate in heptanes] to give 2-(1,3-dimethyl- 1H- pyrazol-4-yl)acetaldehyde (0.037 g, 0.27 mmol, 20% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 9.67 (t, J = 2.1 Hz, 1H), 7.25 (s, 1H), 3.82 (s, 3H), 3.49 (dd, J = 2.1, 0.6 Hz, 2H), 2.18 (s, 3H).

Example 158: 5-{2-[2-(1,5-dimethyl-1H- pyrazol -4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 257)

Example 158A: 5-{6-(benzyloxy)-2-[2-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00664] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.15 mmol, Example 93A) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(1,5-dimethyl- 1H- pyrazol-4-yl)acetaldehyde (0.032 g, 0.23 mmol, Example 158D) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 14 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate (50 ml) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 25 ml). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.068 g, 0.13 mmol, 86% yield over two steps). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.50-7.44 (m, 2H), 7.37-7.32 (m, 2H), 7.32-7.28 (m, 1H), 7.27 (s, 1H), 6.88 (s, 1H), 5.14 (s, 2H), 4.35 (br s, 2H), 4.00 (s, 2H), 3.66 (s, 3H), 3.49 (br s, 2H), 3.32 (dd, J = 10.4, 6.4 Hz, 2H), 3.05 (t, J = 5.3 Hz, 2H), 2.83 (dd, J = 9.7, 7.0 Hz, 2H), 2.18 (s, 3H); MS (ESI ⁺ ) m/z 513.9 [M+H] ⁺ .

Example 158B: 5-{2-[2-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00665] A vial containing a suspension of 5-{6-(benzyloxy)-2-[2-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.064 g, 0.12 mmol) and 1,2,3,4,5-pentamethylbenzene (0.055 g, 0.37 mmol) in dichloromethane (1.2 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (0.99 mL, 0.99 mmol) was then added. The resulting mixture was stirred at -78°C for 10 min, then the dry ice-acetone bath was replaced with an ice-water bath. After 60 min, the mixture was recooled to -78°C, diluted with dichloromethane (3 mL), and quenched by the successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.041 g, 0.097 mmol, 78% yield). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.27 (s, 1H), 6.59 (s, 1H), 4.29 (br s, 2H), 4.00 (s, 2H), 3.65 (s, 3H), 3.47 (br s, 2H), 3.29 (t, J = 8.5 Hz, 2H), 3.01 (t, J = 6.2 Hz, 2H), 2.81 (dd, J =9.6, 7.7 Hz, 2H), 2.16 (s, 3H); MS (ESI ⁺ ) m/z 423.8 [M+H] ⁺ .

Example 158C: 4-(2-methoxyvinyl)-1,5-dimethyl-1H-pyrazole

[00666] (Methoxymethyl)triphenylphosphonium chloride (1.62 g, 4.71 mmol) and tetrahydrofuran (6.0 mL) were added to the flask. The flask was cooled to 0 °C, then potassium 2-methylpropan-2-olate (1.0 M in tetrahydrofuran) (4.4 mL, 4.4 mmol) was added. Fifteen minutes later, a solution of 1,5-dimethyl-1 H -pyrazole-4-carbaldehyde (0.450 g, 3.62 mmol) in tetrahydrofuran (6.0 mL) was added. The resulting mixture was stirred at 0 °C for 2 hours and then at ambient temperature for 46 hours. The mixture was then poured into saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (4 x 25 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [12 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound as a mixture of olefin isomers [50:50 ( E )-( Z )] (0.408 g, 2.68 mmol, 74% yield). Data for the mixture of isomers: ¹ H NMR (600 MHz, _CDCl3 ) δ ppm. 7.78 (s, 1H), 7.35 (s, 1H), 6.73 (d, J =12.9 Hz, 1H), 6.01 (d, J =6.5 Hz, 1H), 5.52 (d, J =12.9 Hz, 1H), 5.04 (dd, J =6.5, 0.5 Hz, 1H), 3.75 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.64 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H); MS (ESI ⁺ ) m/z 153.3 [M+H] ⁺ .

Example 158D: 2-(1,5-dimethyl-1H-pyrazol-4-yl)acetaldehyde

[00667] 4-(2-methoxyvinyl)-1,5-dimethyl- 1H- pyrazole (0.200 g, 1.31 mmol) and tetrahydrofuran (6.6 mL) were added to the vial. The vial was cooled to 0 °C. The solution was treated with 6.0 M hydrochloric acid (6.6 mL, 39 mmol) and then the ice bath was removed. The vial was allowed to warm to ambient temperature and then heated to 50 °C. After 16 h, the vial was cooled to ambient temperature and the solution was transferred to a beaker containing saturated aqueous sodium bicarbonate (60 mL). The resulting mixture was stirred for 15 min and then extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography [12 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound (0.035 g, 0.25 mmol, 19% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm 9.63 (t, J = 2.3 Hz, 1H), 7.33 (s, 1H), 3.79 (s, 3H), 3.46 (d, J = 2.3 Hz, 2H), 2.18 (s, 3H).

Example 159: N -(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 258)

Example 159A: 6-(benzyloxy)-N-(cyclopropylmethyl)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00668] The product of Example 54A (39.1 mg, 0.1 mmol) was dissolved in acetonitrile (1 mL). N,N -diisopropylethylamine (87 µL, 0.5 mmol) and triphosgene (10.4 mg, 0.035 mmol) in acetonitrile (1 mL) were added sequentially and the mixture was stirred at room temperature for 20 min. Cyclopropylmethanamine (0.29 M in 5:2 N,N -dimethylformamide/acetonitrile, 700 µL) was then added and the mixture was stirred for 1 h at room temperature. The reaction mixture was directly purified by preparative reverse phase HPLC on a Phenomenex ^® Luna ^® C8(2) 5 µm 100 AXIA™ (50 mm x 30 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used at a flow rate of 40 mL/min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to afford the title compound. MS (APCI ⁺ ) m/z 489.1 [M+H] ⁺ .

Example 159B: N-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00669] A mixture of the above product from Example 159A and 5% Pd/C (5 mg) in methanol (5 mL) was stirred under hydrogen atmosphere (45 psi) at room temperature overnight. The crude reaction mixture was filtered through a pad of diatomaceous earth and concentrated. The residue was reconstituted in methanol (2 mL) and purified by reverse phase preparative HPLC on a Waters XBridge™ C8 5 μm (75 mm x 30 mm) column. A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used at a flow rate of 40 mL/min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min, linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (13.5 mg, 0.034 mmol, 34% yield over two steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.38-6.86 (m, 2H), 6.74 (t, J =5.5 Hz, 1H), 6.51 (s, 1H), 4.38 (s, 2H), 3.95 (s, 2H), 3.52 (t, J =5.8 Hz, 2H), 2.93 (dd, J =6.7, 5.5 Hz, 2H), 2.67 (t, J =5.5 Hz, 2H), 1.04-0.88 (m, 1H), 0.44-0.32 (m, 2H), 0.19-0.12 (m, 2H); MS (CIAD ⁺ ) m/z 399.2 [M+H] ⁺ .

Example 160: 5-{(7S ) -7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 259)

[00670] The product of Example 124B (150 mg, 0.381 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 supplied by a 350 psi dewar of bone dry non-certified _CO2 with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 40% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm × 250 mm id CHIRALPAK® IC column with 5 μm particles. The enantiomer peak eluted early to give the title compound (61.5 mg, 0.156 mmol, 82% yield). ¹ H NMR and MS data were identical to those of Example 124B. The absolute stereochemistry was tentatively assigned by analogy with the chromatographic elution order for the product of Example 18.

Example 161: 5-{(7 R )-7-[(3,3-difluoropropyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 260)

[00671] The product of Example 124B (150 mg, 0.381 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 supplied by a dewar of bone dry non-certified _CO2 at 350 psi with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 40% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm × 250 mm id CHIRALPAK® IC column with 5 μm particles. The later eluting enantiomer peak gave the title compound (55.0 mg, 0.140 mmol, 73.3% yield). ¹ H NMR and MS data were identical to those of Example 124B. The absolute stereochemistry was tentatively assigned by analogy with the chromatographic elution order for the product of Example 19.

Example 162: 8-fluoro-6-hydroxy- N -[(oxan-4-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 261)

Example 162A: 6-(benzyloxy)-8-fluoro-N-[(oxan-4-yl)methyl]-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00672] The title compound was prepared from (tetrahydro- 2H -pyran-4-yl)methanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 533.2 [M+H] ⁺ .

Example 162B: 8-fluoro-6-hydroxy-N-[(oxan-4-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00673] The title compound was prepared from Example 162A above using the procedures described for Example 159B in 37% yield (for 2 steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 6.68 (t, J =5.6 Hz, 1H), 6.49 (s, 1H), 4.36 (s, 2H), 3.94 (s, 2H), 3.82 (ddd, J =11.1, 4.1, 1.8 Hz, 2H), 3.50 (t, J =5.8 Hz, 2H), 3.27-3.18 (m, 2H), 2.93 (dd, J =6.9, 5.6 Hz, 2H), 2.65 (t, J =5.7 Hz, 2H), 1.72-1.61 (m, 1H), 1.57-1.50 (m, 2H), 1.16-1.04 (m, 2H); MS (CIAD ⁺ ) m/z 433.3 [M+H] ⁺ .

Example 163: N -[(3,3-difluorocyclobutyl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 262)

Example 163A: 6-(benzyloxy)-N-[(3,3-difluorocyclobutyl)methyl]-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00674] The title compound was prepared from (3,3-difluorocyclobutyl)methanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 539.1 [M+H] ⁺ .

Example 163B: N-[(3,3-difluorocyclobutyl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00675] The title compound was prepared from Example 163A above using the procedures described for Example 159B in 46% yield (for 2 steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 6.82 (t, J =5.6 Hz, 1H), 6.49 (s, 1H), 4.36 (s, 2H), 3.94 (s, 2H), 3.50 (t, J =5.8 Hz, 2H), 3.16 (t, J =5.8 Hz, 2H), 2.65 (t, J =5.8 Hz, 2H), 2.56 (ddd, J = 14.3, 8.8, 5.5 Hz, 2H), 2.31-2.24 (m, 3H); MS (CIAD ⁺ ) m/z 449.2 [M+H] ⁺ .

Example 164: 8-fluoro-6-hydroxy- N -[(oxolan-2-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 263)

Example 164A: 6-(benzyloxy)-8-fluoro-N-[(oxolan-2-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00676] The title compound was prepared from (tetrahydrofuran-2-yl)methanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 519.2 [M+H] ⁺ .

Example 164B: 8-fluoro-6-hydroxy-N-[(oxolan-2-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00677] The title compound was prepared from Example 164A above using the procedures described for Example 159B in 31% yield (over 2 steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 6.71 (t, J =5.7 Hz, 1H), 6.51-6.47 (m, 1H), 4.36 (s, 2H), 3.94 (s, 2H), 3.85 (p, J =6.3 Hz, 1H), 3.77-3.69 (m, 1H), 3.65-3.54 (m, 1H), 3.50 (t, J =5.8 Hz, 2H), 3.15-3.01 (m, 2H), 2.68-2.62 (m, 2H), 1.88-1.71 (m, 3H), 1.58-1.47 (m, 1H); MS (CIAD ⁺ ) m/z 429.2 [M+H] ⁺ .

Example 165: N -(2-cyclopropylethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 264)

Example 165A: 6-(benzyloxy)-N-(2-cyclopropylethyl)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00678] The title compound was prepared from 2-cyclopropylethane-1-amine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 503.1 [M+H] ⁺ .

Example 165B: N-(2-cyclopropylethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00679] The title compound was prepared from Example 165A above using the procedures described for Example 159B in 28% yield (for 2 steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 6.63 (t, J =5.5 Hz, 1H), 6.48 (s, 1H), 4.35 (s, 2H), 3.93 (s, 2H), 3.49 (t, J =5.8 Hz, 2H), 3.15-3.06 (m, 2H), 2.68-2.60 (m, 2H), 1.32 (k, J =7.1 Hz, 2H), 0.76-0.55 (m, 1H), 0.37 (dd, J =8.1, 1.7 Hz, 2H), 0.12 - -0.07 (m, 2H); MS (CIAD ⁺ ) m/z 413.2 [M+H] ⁺ .

Example 166: N -[(1,3-dimethyl-1 H -pyrazol-5-yl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 265)

Example 166A: 6-(benzyloxy)-N-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00680] The title compound was prepared from (1,3-dimethyl-1H-pyrazol-5-yl)methanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 543.1 [M+H] ⁺ .

Example 166B: N-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00681] The title compound was prepared from Example 166A above using the procedures described for Example 159B in 5% yield (for 2 steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.12 (t, J = 5.5 Hz, 1H), 6.49 (s, 1H), 5.86 (s, 1H), 4.38 (s, 2H), 4.21 (d, J = 5.5 Hz, 2H), 3.93 (s, 2H), 3.67 (s, 3H), 3.52 (t, J = 5.8 Hz, 2H), 2.69-2.63 (m, 2H), 2.06 (s, 3H); MS (CIAD ⁺ ) m/z 453.3 [M+H] ⁺ .

Example 167: 5-{2-[2-(1- tert -butyl-3,5-dimethyl-1H - pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 266)

Example 167A: 5-(6-(benzyloxy)-2-(2-(1-(tert-butyl)-3,5-dimethyl-1H-pyrazol-4-yl)ethyl)-8-fluoro-1,2,3, 4-tetrahydroisoquinolin-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[00682] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.15 mmol, Example 93A) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(1-( tert -butyl)-3,5-dimethyl- 1H- pyrazol-4-yl)acetaldehyde (0.045 g, 0.23 mmol, Example 167D) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 36 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 ml) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 25 ml). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.074 g, 0.13 mmol, 85% yield over two steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 9.83 (br s, 1H), 7.50 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 6.90 (s, 1H), 5.17 (s, 2H), 4.62 (br s, 1H), 4.23 (br s, 1H), 3.97 (s, 2H), 3.81 (br s, 1H), 3.16 (br s, 2H), 3.06 (s, 2H), 2.76 (s, 2H), 2.34 (s, 3H), 2.09 (s, 3H), 1.52 (s, 9H); MS (CIAD ⁺ ) m/z 570.4 [M+H] ⁺ .

Example 167B: 5-{2-[2-(1-tert-butyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00683] A vial containing a suspension of 5-(6-(benzyloxy)-2-(2-(1-(tert-butyl)-3,5-dimethyl- 1H- pyrazol-4-yl)ethyl)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.071 g, 0.13 mmol) and 1,2,3,4,5-pentamethylbenzene (0.056 g, 0.38 mmol) in dichloromethane (1.3 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.0 mL, 1.0 mmol) was then added. The resulting mixture was stirred at -78°C for 10 min, then the dry ice-acetone bath was replaced with an ice-water bath. After 60 min, the mixture was recooled to -78°C, diluted with dichloromethane (3 mL), and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.057 g, 0.12 mmol, 94% yield). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm 6.60 (s, 1H), 4.30 (br s, 2H), 4.02 (s, 2H), 3.47 (br s, 2H), 3.12 (dd, J = 11.4, 6.2 Hz, 2H), 3.02 (t, J = 5.7 Hz, 2H), 2.73 (dd, J = 9.3, 6.0 Hz, 2H), 2.28 (s, 3H), 2.05 (s, 3H), 1.47 (s, 9H); MS (APCI ⁺ ) m/z 480.3 [M+H] ⁺ .

Example 167C: 1-(tert-butyl)-4-(2-methoxyvinyl)-3,5-dimethyl-1H-pyrazole

[00684] (Methoxymethyl)triphenylphosphonium chloride (1.11 g, 3.25 mmol) and tetrahydrofuran (4.2 mL) were added to the flask. The flask was cooled to 0 °C, then potassium 2-methylpropan-2-olate (1.0 M in tetrahydrofuran) (3.0 mL, 3.0 mmol) was added. Fifteen minutes later, a solution of 1-( tert- butyl)-3,5-dimethyl-1 H -pyrazole-4-carbaldehyde (0.450 g, 2.50 mmol) in tetrahydrofuran (4.2 mL) was added. The resulting mixture was stirred at 0 °C for 1 hour and then at ambient temperature for 17 hours. The mixture was then poured into saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (4 x 25 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [40 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound as a mixture of olefin isomers [73:27 ( E )-( Z )] (0.444 g, 2.13 mmol, 85% yield). Data for the ( E )-isomer: ¹ H NMR (500 MHz, _CDCl3 ) δ ppm. 6.52 (d, J = 13.0 Hz, 1H), 5.50 (d, J = 13.0 Hz, 1H), 3.65 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 1.61 (s, 9H). Data for ( Z )-isomer: ¹ H NMR (500 MHz, _CDCl3 ) δ ppm 6.01 (d, J = 6.7 Hz, 1H), 4.99 (d, J = 6.7 Hz, 1H), 3.65 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H), 1.61 (s, 9H); MS (APCI ⁺ ) m/z 209.7 [M+H] ⁺ .

Example 167D: 2-(1-(tert-butyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetaldehyde

[00685] To the vial were added 1-( tert -butyl)-4-(2-methoxyvinyl)-3,5-dimethyl- 1H- pyrazole (0.200 g, 0.960 mmol) and tetrahydrofuran (4.8 mL). The vial was cooled to 0 °C. The solution was treated with 6.0 M hydrochloric acid (4.8 mL, 29 mmol) and then the ice bath was removed. The vial was allowed to warm to ambient temperature and then heated to 50 °C. After 3 h, the vial was cooled to ambient temperature and the solution was transferred to a beaker containing saturated aqueous sodium bicarbonate (60 mL). The resulting mixture was stirred for 15 min and then extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography [4 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound (0.169 g, 0.870 mmol, 91% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.53 (t, J = 2.6 Hz, 1H), 3.37 (d, J = 2.6 Hz, 2H), 2.31 (s, 3H), 2.17 (s, 3H), 1.62 (s, 9H); MS (ESI ⁺ ) m/z 195.5 [M+H] ⁺ .

Example 168: 5-[2-(aminomethyl)-4-fluoro-6-hydroxy-2,3-dihydro-1H - inden-5-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 267)

Example 168A: 5-(benzyloxy)-7-fluoro-2,3-dihydro-1H-inden-1-one

[00686] To a mixture of 5-bromo-7-fluoro-2,3-dihydro- 1H -inden-1-one (59 g, 232 mmol), water (20.88 mL, 1159 mmol), and cesium carbonate (177 g, 543 mmol) in N,N -dimethylformamide (600 mL) was added RockPhos Pd G3 precatalyst (1.944 g, 2.318 mmol) under nitrogen atmosphere at 25 °C. The mixture was heated to 60 °C and stirred for 12 h at 60 °C under N ₂ atmosphere. Then, the mixture was cooled to 25 °C. Benzyl bromide (33.0 mL, 278 mmol) was added to the mixture, and the mixture was stirred for 2 h at 25 °C. One additional 59 g vial (relative to 5-bromo-7-fluoro-2,3-dihydro- 1H -inden-1-one) was set up in parallel as described above. The two reaction mixtures were combined and diluted with water (2 L) and ethyl acetate (800 mL). The resulting mixture was then filtered through diatomaceous earth. The two phases of the filtrate were separated and the aqueous phase was extracted with ethyl acetate (2 x 800 mL). The combined organic phases were washed with brine (3 x 500 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (0-10%) to give the title compound (76 g, 267 mmol, 57.6% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 7.46-7.35 (m, 5H), 6.81-6.76 (m, 1H), 6.61 (dd, J= 10.88, 1.88 Hz, 1H), 5.13 (s, 2H), 3.12-3.06 (m, 2H), 2.73-2.67 (m, 2H).

Example 168B: 5-(benzyloxy)-2-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one

[00687] To a solution of the product from Example 168A (25 g, 88 mmol) in chloroform (125 mL) and ethyl acetate (125 mL) was added copper (II) bromide (23.53 g, 105 mmol) at 25 °C. The mixture was then stirred for 2 hours at 80 °C. Copper (II) bromide (23.53 g, 105 mmol) was then added to the reaction mixture at 25 °C and the mixture was stirred for 2 hours at 80 °C. One additional 20 g vial and one additional 25 g vial were set up in parallel as described above. The three reaction mixtures were combined and filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with petroleum ether/ethyl acetate 5:1 and filtered. The cake on the filter was the title compound. The filtrate was purified by flash column chromatography (petroleum ether/ethyl acetate, 10:1) and combined with the filter cake to give the title compound (67.5 g, 181 mmol, 73.7% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 7.47-7.35 (m, 5H), 6.78-6.74 (m, 1H), 6.67 (dd, J= 10.63, 1.88 Hz, 1H), 5.19-5.12 (m, 2H), 4.62 (dd, J= 7.50, 3.13 Hz, 1H), 3.78 (dd, J= 18.39, 7.50 Hz, 1H), 3.37 (dd, J= 18.39, 3.13 Hz, 1H).

Example 168C: 5-(benzyloxy)-7-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carbonitrile

[00688] To a solution of sodium cyanide (18.6 g, 380 mmol) in N,N -dimethylformamide (280 mL) and water (40 mL) was added a solution of the product from Example 168B (42.5 g, 114 mmol) in N,N -dimethylformamide (120 mL) dropwise at 0 °C. The mixture was then stirred for 30 minutes at 25 °C. One additional 1 g vial, one additional 2.8 g vial, one additional 7.6 g vial, and one additional 25 g vial were set up in parallel as described above. The mixture was then diluted with water (4 L) and purified by reverse phase column chromatography (Agel Claricep™ Flash AQ C18, 20-35 μm, 100 , 800 g, flow rate 100 ml/min, 0-100% gradient of acetonitrile in water, wavelength: 220 and 254 nm). The eluent was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluting with tetrahydrofuran/petroleum ether (0-30%) to give the title compound (45.2 g, 145 mmol, yield 69.3%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.52-7.31 (m, 6H), 7.09 (s, 1H), 7.01 (br d, J = 11.51 Hz, 1H), 5.27 (s, 2H).

Example 168D: 5-(benzyloxy)-7-fluoro-1-hydroxy-2,3-dihydro-1H-indene-2-carbonitrile

[00689] To a solution of the product from Example 168C (30 g, 96 mmol) in methanol (300 mL) and tetrahydrofuran (300 mL) was added sodium borohydride (5.45 g, 144 mmol) in portions at 0 °C. The mixture was then stirred for 2 h at 25 °C. Three additional 500 mg vials, one additional 5.7 g vial, and one additional 8 g vial were set up in parallel as described above. The six reactions were combined, quenched with water (1500 mL), and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluting with petroleum ether/tetrahydrofuran (10:1 to 5:1, 10:1 by-product, 5:1 product) to give the title compound (35 g, 111 mmol, 77% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 7.41 (d, J= 4.38 Hz, 5H), 6.67 (dt, J= 5.38 Hz, 1H), 6.62 (dt, J= 10.76, 2.44 Hz, 1H), 5.67 (t, J= 4.63 Hz, 1H), 5.48 (t, J= 5.38 Hz, 1H), 5.06 (s, 2H), 3.54-3.33 (m, 2H), 3.30-3.08 (m, 1H), 2.52 (d, J= 4.88 Hz, 1H), 2.38 (d, J= 5.38 Hz, 1H).

Example 168E: 2-(aminomethyl)-7-fluoro-2,3-dihydro-1H-inden-5- ol hydrochloride

[00690] To a mixture of Pd-C (5 g, 4.70 mmol) in methanol (500 mL) and HCl (50 mL, 600 mmol) was added the product from Example 168D (10 g, 31.8 mmol) at 25 °C. The mixture was then stirred for 48 h at 25 °C under H ₂ (15 psi). One additional 10 g vial was set up in parallel as described above. The two reaction mixtures were combined and filtered through diatomaceous earth washed with methanol (1000 mL). The filtrate was evaporated under reduced pressure to give the title compound (13.7 g, 56.6 mmol, 89% yield), which was used directly in the next step. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.11-9.26 (m, 1H), 8.14 (lat s, 3H), 6.49 (s, 1H), 6.36 (dd, J= 10.88, 1.50 Hz, 1H), 2.83-3.02 (m, 4H), 2.77 -2.55 (m, 3H).

Example 168F: tert-butyl [(4-fluoro-6-hydroxy-2,3-dihydro-1H-inden-2-yl)methyl]carbamate

[00691] To a solution of the product from Example 168E (15.2 g, 62.8 mmol) in tetrahydrofuran (150 mL) and water (150 mL) was added sodium bicarbonate (26.4 g, 314 mmol) followed by di-tert-butyl dicarbonate (21.89 mL, 94 mmol) dropwise at 0 °C. The mixture was then stirred for 12 h at 25 °C. One additional 500 mg vial and one additional 6 g vial were set up in parallel as described above. The three reactions were combined. The resulting mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (20:1-5:1) to give the title compound (21.4 g, 72.3 mmol, 80% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.48 (s, 1H), 6.38 (br d, J= 10.13 Hz, 1H), 4.71 (br s, 1H), 3.29-3.14 (m, 1H), 3.29-3.14 (m, 1H), 3.05-2.91(m, 2H), 2.75-2.50 (m, 3H), 1.46 (d, J= 1.50 Hz, 10H).

Example 168G: tert-butyl ({4-fluoro-6-[(2-methoxyethoxy)methoxy]-2,3-dihydro-1H-inden-2-yl}methyl)carbamate

[00692] To a solution of the product from Example 168F (5.6 g, 17.92 mmol) in anhydrous tetrahydrofuran (150 mL) was added cesium carbonate (8.76 g, 26.9 mmol) at 25 °C, and then 2-methoxyethoxymethyl chloride (2.435 mL, 21.50 mmol) was added dropwise at 0 °C. The mixture was then stirred for 1 hour at 0 °C. Thin layer chromatography (phosphomolybdic acid, petroleum ether:ethyl acetate = 3:1) showed that 50% of the starting material remained. Then cesium carbonate (5.84 g, 17.92 mmol) and 2-methoxyethoxymethyl chloride (2.029 mL, 17.92 mmol) were added to the mixture and stirred for 1 h at 0 °C. Thin layer chromatography (phosphomolybdic acid, petroleum ether:ethyl acetate = 3:1) showed that 50% of the starting material still remained. One additional 1.3 g vial and one additional 5.6 g vial were set up in parallel as described above. These three reactions were combined. The combined reaction mixtures were diluted with water (600 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. Two additional 2 g vials were set up as described above. The crude products were combined and purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (10-12%) to give a mixture of the products of Examples 168F and 168G (18 g), which was used immediately. To a solution of the products of Examples 168F and 168G (1 g, 3.55 mmol) in acetone (10 mL) was added cesium carbonate (1.737 g, 5.33 mmol) at 25 °C, followed by 2-methoxyethoxymethyl chloride (0.483 mL, 4.27 mmol) dropwise at 0 °C. The mixture was then stirred for 1 h at 0 °C. Seventeen additional 1 g vials were set up in parallel as described above. These reactions were combined. The resulting mixture was diluted with water (600 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (10-12%) to give the title compound (17 g, 41.4 mmol, 64.7% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 6.71 (s, 1H), 6.61-6.54 (m, 1H), 5.22 (s, 2H), 4.66 (br s, 1H), 3.81 (dd, J= 5.50, 3.88 Hz, 2H), 3.57 (dd, J= 5.44, 3.81 Hz, 3H), 3.39 (s, 3H), 3.20 (br d, J= 5.50 Hz, 2H), 3.03 (br dd, J= 15.51, 7.50 Hz, 2H), 1.46 (s, 9H), 2.55-2.75 (m, 3H).

Example 168H: tert-butyl ({4-fluoro-5-iodo-6-[(2-methoxyethoxy)methoxy]-2,3-dihydro-1H-inden-2-yl}methyl)carbamate

[00693] To a solution of the product of Example 168G (5.9 g, 14.37 mmol) in anhydrous tetrahydrofuran (150 mL) was added n -butyl lithium (34.5 mL, 86 mmol) dropwise at -70 °C under N ₂ . The mixture was stirred for 60 min at -70 °C under N ₂ . A solution of I ₂ (23.71 g, 93 mmol) in tetrahydrofuran (30 mL) was then added at -70 °C under N ₂ . The mixture was stirred for 60 min at -70 °C under N ₂ . The mixture was then quenched with a saturated aqueous solution of NH ₄ Cl and a saturated aqueous solution of Na ₂ S ₂ O ₃ (1:1, 500 mL) dropwise. The resulting solution was extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. One additional 5 g and one additional 5.9 g vials were set up in parallel as described above. These crude products were combined and purified by column chromatography on silica gel eluting with ethyl acetate:petroleum ether = 15-20% to give the title compound (14.5 g, 26.3 mmol, 64.3% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 6.80 (s, 1H), 5.31 (s, 2H), 4.66 (br s, 1H), 3.93-3.82 (m, 2H), 3.63-3.54 (m, 2H), 3.39 (s, 3H), 3.26-3.13 (m, 2H), 3.12-2.99 (m, 2H), 2.75-2.61 (m, 3H), 1.46 (s, 9H).

Example 168I: tert-butyl [(2-{[(tert-butoxycarbonyl)amino]methyl}-4-fluoro-6-[(2-methoxyethoxy)methoxy]-2,3-dihydro-1H-inden-5-yl)amino]acetate

[00694] To a solution of the product of Example 168H (2 g, 3.63 mmol) in dioxane (20 mL) was added cesium carbonate (3.55 g, 10.90 mmol) followed by tert -butyl 2-aminoacetate (1.430 g, 10.90 mmol) at 25 °C. The precatalyst BrettPhos Pd G3 (0.725 g, 0.799 mmol) was then added under a nitrogen atmosphere. The mixture was then stirred for 4 h at 95 °C under N ₂ . One additional 735 mg vial and six additional 2 g scale vials were set up in parallel as described above. The resulting mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether = 11-18%) to give the title compound (10 g, 19.05 mmol, 70.9% yield). ¹ H NMR: (400 MHz, CDCl ₃ ) δ ppm. 6.77 (s, 1H), 5.26 (s, 2H), 4.64 (br s, 1H), 4.41 (br s, 1H), 3.95 (br s, 2H), 3.89-3.81 (m, 2H), 3.61-3.55 (m, 2H), 3.43-3.35 (m, 3H), 3.19 (br s, 2H), 3.07-2.87 (m, 2H), 2.73-2.50 (m, 3H), 1.46 (s, 18H).

Example 168J: tert-butyl [(2-{[(tert-butoxycarbonyl)amino]methyl}-4-fluoro-6-[(2-methoxyethoxy)methoxy]-2,3-dihydro-1H-inden-5-yl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]acetate

[00695] Allyl alcohol (1.555 mL, 22.86 mmol) was added dropwise to a solution of chlorosulfonyl isocyanate (1.985 mL, 22.86 mmol) in dichloromethane (3 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C under N ₂ . The mixture was then added dropwise to a mixture of the product of Example 168I (6 g, 11.43 mmol) and triethylamine (4.78 mL, 34.3 mmol) in dichloromethane (60 mL) at 0 °C. The resulting mixture was stirred for 2 h at 0 °C under N ₂ . The mixture was then diluted with water (30 mL) and the organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (8.5 g, 12.84 mmol, 112% yield), which was used directly in the next step. MS (ESI ⁺ ) m/z 661 [M + 23, M + 46] ⁺ .

Example 168K: tert-Butyl ({4-fluoro-6-[(2-methoxyethoxy)methoxy]-5-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-2,3-dihydro-1H-inden-2-yl}methyl)carbamate

[00696] To a solution of the product of Example 168J (2.2 g, 3.32 mmol) in anhydrous methanol (22 mL) was added molecular sieves 4 (2.2 g). The resulting mixture was stirred for 10 min at 25 °C. Tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.130 mmol) and sodium methoxide (4.31 g, 19.95 mmol) were then added at 25 °C under nitrogen. The mixture was stirred for 2 h at 60 °C under N ₂ . One additional 200 mg and one additional 2 g vials were set up in parallel as described above. The three reactions were combined. The combined mixture was filtered and the filter cake was washed with water (100 mL) and methanol (20 mL). The filtrate was adjusted to pH = 4 with aqueous HCl (1 mol/L) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with a mixture of brine and aqueous HCl (1 mol/L) (4:1) (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative HPLC [Shimadzu LC-8A preparative HPLC; Agela DuraShell C18 column, 250 × 70 mm × 10 μm, flow rate 130 mL/min, 20-40% over 20 min gradient of acetonitrile in water (10 mM NH ₄ HCO ₃ )]. The eluent solution containing the product was adjusted to pH = 4 with 1 M HCl (aqueous solution) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (1.5 g, 2.83 mmol, 42.6% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.06-6.99 (m, 1H), 6.92 (s, 1H), 5.25 (s, 2H), 4.40 (s, 3H), 3.76-3.69 (m, 2H), 3.45 (dd, J= 5.38, 4.00 Hz, 2H), 3.22 (s, 3H), 3.04-2.86 (m, 4H), 2.68-2.56 (m, 3H), 1.38 (s, 9H).

Example 168L: 5-[2-(aminomethyl)-4-fluoro-6-hydroxy-2,3-dihydro-1H-inden-5-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione 2,2,2-trifluoroacetate

[00697] To a solution of the product of Example 168K (1.3 g, 2.453 mmol) in dichloromethane (18 mL) was added trifluoroacetic acid (6 mL, 78 mmol) dropwise at 0 °C. The mixture was stirred for 2 h at 25 °C. One additional 100 mg vial was set up in parallel as described above. The two reactions were combined. The combined mixtures were evaporated under reduced pressure. The residue was triturated with methanol/water (3:1) to give the title compound (430 mg, 0.989 mmol, 31.5% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 9.13 (br s, 1H), 7.78 (br s, 3H), 6.57 (s, 1H), 3.96 (s, 2H), 3.05-2.86 (m, 4H), 2.77-2.58 (m, 3H); MS (ESI ^- ) m/z 314 [MH] ^- .

Example 169: 5-(4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro- 1H -inden-5-yl) ^-1λ6,2,5 -thiadiazolidine-1,1,3-trione (Compound 268)

[00698] To a suspension of the product of Example 168L (25 mg, 0.058 mmol) in dichloromethane (0.75 mL) and ethanol (0.5 mL) was added triethylamine (0.011 mL, 0.082 mmol). The resulting suspension was stirred at ambient temperature for 5 min. 3-Methylbutanal (8.31 μL, 0.076 mmol) was then added and stirred for an additional 21 h. Sodium tetrahydroborate (5.5 mg, 0.146 mmol) was then added and stirred for an additional 3 h. The reaction mixture was diluted with methanol (5 mL) and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, flow rate 50 mL/min, 10 to 100% _CH3OH in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with _CO2 (s)]) to afford the title compound (11.3 mg, _0.029 mmol, yield 50.3%). ¹ H NMR (400 MHz, DMSO- d6 ) δ ppm 8.99 (s, 1H), 8.13 (s, 2H), 6.55 (s, 1H), 3.89 (s, 2H), 3.03-3.92 (m, 4H), 2.89 (dd, J =9.9, 6.4 Hz, 2H), 2.72 (p, J =7.2 Hz, 1H), 2.66-2.57 (m, 2H), 1.66-1.51 (m, 1H), 1.50-1.40 (m, 2H), 0.86 (d, J =6.6 Hz, 6H); MS (CIAD ⁺ ) m/z 386 [M+H] ⁺ .

Example 170: 5-(2-{[bis(3-methylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H - inden-5-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 269)

[00699] Triethylamine (0.019 mL, 0.140 mmol) was added to a suspension of the product of Example 168L (30 mg, 0.070 mmol) in dichloromethane (1.0 mL). The resulting suspension was stirred at ambient temperature for 5 min. 3-Methylbutanal (9.20 μL, 0.084 mmol) dissolved in dichloromethane (1.0 mL) was then added and the reaction mixture was stirred for an additional 10 min. Sodium triacetoxyhydroborate (37.0 mg, 0.175 mmol) was then added and the reaction mixture was stirred at ambient temperature. After 14 h, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (20 mL) and stirred at ambient temperature for 20 min. The mixture was then extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by reverse phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 50 mL/min flow rate, 10 to 100% _CH3OH in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with _CO2 (s)]) to afford the title compound (18.4 mg, 0.040 mmol, 57.8% yield). ¹ H NMR (600 MHz, DMSO _-d6 ) δ ppm. 9.07 (s, 1H), 8.86 (s, 1H), 6.58 (s, 1H), 3.92 (s, 2H), 3.27 (s, 2H), 3.16-3.05 (m, 6H), 2.86 (s, 1H), 2.70-2.60 (m, 2H), 1.65-1.58 (m, 2H), 1.54 (s, 4H), 0.92 (d, J =6.5 Hz, 12H); MS (CIAD ⁺ ) m/z 456 [M+H] ⁺ .

Example 171: 8-fluoro-6-hydroxy- N -[(oxolan-3-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 270)

Example 171A: 6-(benzyloxy)-8-fluoro-N-[(oxolan-3-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00700] The title compound was prepared from (tetrahydrofuran-3-yl)methanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 531.2 [M+H] ⁺ .

Example 171B: 8-fluoro-6-hydroxy-N-[(oxolan-3-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00701] The title compound was prepared from Example 171A above using the procedures described for Example 159B in 29% yield (for 2 steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 6.78 (t, J =5.6 Hz, 1H), 6.49 (s, 1H), 4.36 (s, 2H), 3.94 (s, 2H), 3.69 (td, J =8.0, 5.7 Hz, 1H), 3.65-3.55 (m, 2H), 3.50 (t, J =5.8 Hz, 2H), 3.42 (dd, J =8.5, 5.2 Hz, 1H), 3.08-2.96 (m, 2H), 2.65 (t, J =5.8 Hz, 2H), 2.41-2.32 (m, 1H), 1.87 (dtd, J =12.2, 8.0, 5.7 Hz, 1H), 1.58-1.49 (m, 1H); MS (CIAD ⁺ ) m/z 429.2 [M+H] ⁺ .

Example 172: N -[(1,5-dimethyl-1 H -pyrazol-4-yl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 271)

Example 172A: 6-(benzyloxy)-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00702] The title compound was prepared from (1,5-dimethyl-1H-pyrazol-4-yl)methanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 543.2 [M+H] ⁺ .

Example 172B: N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00703] The title compound was prepared from Example 172A above using the procedures described for Example 159B in 19% yield (for 2 steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.00 (t, J = 5.7 Hz, 1H), 6.49 (s, 1H), 5.86 (s, 1H), 4.37 (s, 2H), 4.10 (d, J = 5.7 Hz, 2H), 3.93 (s, 2H), 3.62 (s, 3H), 3.51 (t, J = 5.8 Hz, 2H), 2.65 (t, J = 5.5 Hz, 2H), 2.17 (d, J = 0.7 Hz, 3H); MS (CIAD ⁺ ) m/z 453.3 [M+H] ⁺ .

Example 173: 8-fluoro-6-hydroxy- N -[(1-methyl-1 H -pyrazol-5-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 272)

Example 173A: 6-(benzyloxy)-8-fluoro-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00704] The title compound was prepared from (1-methyl- 1H- pyrazol-5-yl)methanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 529.1 [M+H] ⁺ .

Example 173B: 8-fluoro-6-hydroxy-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00705] The title compound was prepared from Example 172A above using the procedures described for Example 159B in 18% yield (for 2 steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 7.25 (d, J =1.8 Hz, 1H), 7.16 (t, J =5.5 Hz, 1H), 6.55-6.46 (m, 1H), 6.09 (d, J =1.8 Hz, 1H), 4.39 (s, 2H), 4.28 (d, J =5.5 Hz, 2H), 3.93 (s, 2H), 3.77 (s, 3H), 3.53 (t, J =5.8 Hz, 2H), 2.66 (t, J =5.8 Hz, 2H); MS (CIAD ⁺ ) m/z 439.3 [M+H] ⁺ .

Example 174: 5-(2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H - pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 273)

Example 174A: 5-[6-(benzyloxy)-2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]ethyl}-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00706] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.15 mmol, Example 93A) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(1-isopropyl-3,5-dimethyl- 1H- pyrazol-4-yl)acetaldehyde (0.041 g, 0.23 mmol, Example 174D) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 13 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 25 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.077 g, 0.14 mmol, 90% yield over two steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 9.88 (br s, 1H), 7.54-7.47 (m, 2H), 7.38-7.33 (m, 2H), 7.32-7.28 (m, 1H), 6.91 (s, 1H), 5.17 (s, 2H), 4.62 (br s, 1H), 4.39 (hept, J = 6.6 Hz, 1H), 4.24 (br s, 1H), 3.97 (s, 2H), 3.81 (br s, 1H), 3.20 (br s, 3H), 3.07 (br s, 2H), 2.78 (t, J = 8.6 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H), 1.30 (d, J =6.5 Hz, 6H); MS (CIAD ⁺ ) m/z 556.4 [M+H] ⁺ .

Example 174B: 5-(2-{2-[3,5-dimethyl-1-(propan-2-yl)-1H-pyrazol-4-yl]ethyl}-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00707] A vial containing a suspension of 5-[6-(benzyloxy)-2-{2-[3,5-dimethyl-1-(propan-2-yl) -1H- pyrazol-4-yl]ethyl}-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.074 g, 0.13 mmol) and 1,2,3,4,5-pentamethylbenzene (0.059 g, 0.40 mmol) in dichloromethane (1.3 mL) was cooled to -78 °C with stirring under nitrogen atmosphere. Trichloroborane (1.0 M in dichloromethane) (1.1 mL, 1.1 mmol) was then added. The resulting mixture was stirred at -78°C for 10 min, then the dry ice-acetone bath was replaced with an ice-water bath. After 60 min, the mixture was recooled to -78°C, diluted with dichloromethane (3 mL), and quenched by the successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.048 g, 0.10 mmol, 78% yield). ¹ H NMR (600 MHz, DMSO -d ₆ ) δ ppm 9.89 (br s, 1H), 9.74 (s, 1H), 6.60 (s, 1H), 4.56 (br s, 1H), 4.39 (hept, J = 6.6 Hz, 1H), 4.20 (br s, 1H), 3.96 (s, 2H), 3.79 (br s, 1H), 3.36 (br s, 1H), 3.19 (br s, 2H), 3.04 (br s, 2H), 2.78 (t, J = 8.6 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H), 1.30 (d, J = 6.6 Hz, 6H); MS (ESI ⁺ ) m/z 466.0 [M+H] ⁺ .

Example 174C: 1-isopropyl-4-(2-methoxyvinyl)-3,5-dimethyl-1H-pyrazole

[00708] (Methoxymethyl)triphenylphosphonium chloride (1.21 g, 3.52 mmol) and tetrahydrofuran (4.5 mL) were added to the flask. The flask was cooled to 0 °C, then potassium 2-methylpropan-2-olate (1.0 M in tetrahydrofuran) (3.3 mL, 3.3 mmol) was added. Fifteen minutes later, a solution of 1-isopropyl-3,5-dimethyl-1 H -pyrazole-4-carbaldehyde (0.450 g, 2.71 mmol) in tetrahydrofuran (4.5 mL) was added. The resulting mixture was stirred at 0 °C for 1 hour and then at ambient temperature for 23 hours. The mixture was then poured into saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (4 x 25 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [40 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound as a mixture of olefin isomers [71:29 ( E )-( Z )] (0.415 g, 2.14 mmol, 79% yield). Data for the ( E )-isomer: ¹ H NMR (400 MHz, _CDCl3 ) δ ppm. 6.55 (d, J = 13.0 Hz, 1H), 5.53 (d, J = 13.0 Hz, 1H), 4.46-4.22 (m, 1H), 3.65 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 1.44 (d, J = 6.6 Hz, 6H). Data for ( Z )-isomer: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 5.98 (d, J =6.8 Hz, 1H), 5.00 (d, J =6.7 Hz, 1H), 4.46-4.22 (m, 1H), 3.66 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.44 (d, J =6.6 Hz, 6H); MS (ESI ⁺ ) m/z 195.5 [M+H] ⁺ .

Example 174D: 2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)acetaldehyde

[00709] To the vial were added 1-isopropyl-4-(2-methoxyvinyl)-3,5-dimethyl-1H-pyrazole (0.206 g, 1.06 mmol) and tetrahydrofuran (5.3 mL). The vial was cooled to 0 °C. The solution was treated with 6.0 M hydrochloric acid (5.3 mL, 32 mmol) and then the ice bath was removed. The vial was allowed to warm to ambient temperature and then heated to 50 °C. After 1 h, the vial was cooled to ambient temperature and the solution was transferred to a beaker containing saturated aqueous sodium bicarbonate (60 mL). The resulting mixture was stirred for 15 min and then extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography [12 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound (0.074 g, 0.41 mmol, 39% yield). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 9.55 (t, J = 2.6 Hz, 1H), 4.42-4.30 (m, 1H), 3.38 (d, J = 2.6 Hz, 2H), 2.18 (s, 3H), 2.15 (s, 3H), 1.45 (d, J = 6.6 Hz, 6H); MS (ESI ⁺ ) m/z 213.5 [M + CH ₃ OH + H] ⁺ .

Example 175: 5-(2-{[(3-cyclopropylpropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H - inden-5-yl)-1λ ^6.2 , 5-thiadiazolidine-1,1,3-trione (Compound 274)

[00710] To a suspension of the product of Example 168L (50 mg, 0.116 mmol) in dichloromethane (1.5 mL) and ethanol (1 mL) was added triethylamine (0.023 mL, 0.163 mmol). The reaction mixture was stirred at ambient temperature for 5 min. 3-Cyclopropylpropanal (0.019 mL, 0.151 mmol) was then added and the reaction mixture was stirred at ambient temperature for 22 h. Sodium tetrahydroborate (11.01 mg, 0.291 mmol) was then added and the resulting mixture was stirred for an additional 2 h at ambient temperature. The reaction mixture was diluted with methanol (10 mL) and concentrated with diatomaceous earth to dryness. The residue was purified by reverse phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, flow rate 50 mL/min, 10 to 100% _CH3OH in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to ₇ with CO2(s)]) to afford the title compound (13.9 mg, 0.035 mmol, yield 30.0%). ¹ H NMR (400 MHz, DMSO- d6 ) δ ppm 6.54 (s, 1H), 3.90 (s, 2H), 3.01-2.86 (m, 4H), 2.86 -2.78 (m, 2H), 2.74-2.55 (m, 3H), 1.62 (p, J =7.6 Hz, 2H), 1.20 (k, J =7.3 Hz, 2H), 0.70-0.59 (m, 1H), 0.42-0.33 (m, 2H), 0.02--0.06 (m, 2H); MS (CIAD ⁺ ) m/z 398 [M+H] ⁺ .

Example 176: 5-(4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H - inden-5-yl)-1λ ^6.2 , 5-thiadiazolidine-1,1,3-trione (Compound 275)

[00711] To a suspension of the product of Example 168L (25 mg, 0.058 mmol) in dichloromethane (0.750 mL) and ethanol (0.5 mL) was added triethylamine (0.011 mL, 0.082 mmol). The reaction mixture was stirred at ambient temperature for 5 min, then freshly distilled isobutyraldehyde (6.95 μL, 0.076 mmol) was added and the resulting mixture was stirred for an additional 17.5 h. Sodium tetrahydroborate (5.51 mg, 0.146 mmol) was then added and the mixture was stirred for 2 h. The reaction mixture was diluted with methanol (10 mL) and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, flow rate 50 mL/min, 10 to 100% _CH3OH in water [buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with CO2(s)]) to give the title compound (8.1 mg, 0.022 mmol, yield 37.5%). ¹ H NMR (600 MHz, DMSO _-d6 ) δ ppm 9.04 (s, 1H), 6.58 (s, 1H), 3.93 (s, 2H), 3.05-2.97 (m, 3H), 2.97 (s, 1H), 2.82-2.75 (m, 1H), 2.75-2.72 (m, 2H), 2.69-2.62 (m, 2H), 1.97-1.89 (m, 1H), 0.96-0.92 (m, 6H); MS (CIAD ⁺ ) m/z 372 [M+H] ⁺ .

Example 177: 5-{2-[2-(1-ethyl-3,5-dimethyl-1H- pyrazol -4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 276)

Example 177A: 5-{6-(benzyloxy)-2-[2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00712] To a vial containing 5-[6-(benzyloxy)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt (theoretical 0.15 mmol, Example 93A) were added 1,2-dichloroethane (0.77 mL) and triethylamine (0.043 mL, 0.31 mmol). The mixture was stirred for 5 min, then 2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)acetaldehyde (0.038 g, 0.23 mmol, Example 177D) was added. After 30 min, sodium triacetoxyhydroborate (0.081 g, 0.38 mmol) was added. After 13 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 ml) with dichloromethane. The resulting biphasic mixture was stirred for 20 min. The layers were then separated and the aqueous phase was extracted with dichloromethane (4 x 25 ml). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.074 g, 0.14 mmol, 89% yield over two steps). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm 7.45 (d, J =7.1 Hz, 2H), 7.33 (t, J =7.4 Hz, 2H), 7.28 (dd, J =8.4, 6.1 Hz, 1H), 6.88 (s, 1H), 5.12 (s, 2H), 4.34 (br s, 2H), 4.02 (s, 2H), 3.90 (k, J =7.2 Hz, 2H), 3.49 (lat s, 2H), 3.16 (t, J =8.2 Hz, 2H), 3.06 (t, J =6.2 Hz, 2H), 2.84-2.68 (m, 2H), 2.14 (s, 3H), 2.07 (s, 3H), 1.19 (t, J =7.2 Hz, 3H); MS (CIAD ⁺ ) m/z 542.3 [M+H] ⁺ .

Example 177B: 5-{2-[2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00713] A vial containing a suspension of 5-{6-(benzyloxy)-2-[2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.070 g, 0.13 mmol) and 1,2,3,4,5-pentamethylbenzene (0.058 g, 0.39 mmol) in dichloromethane (1.3 mL) was cooled to -78 °C with stirring under nitrogen atmosphere. Trichloroborane (1.0 M in dichloromethane) (1.0 mL, 1.0 mmol) was then added. The resulting mixture was stirred at -78°C for 10 min, then the dry ice-acetone bath was replaced with an ice-water bath. After 60 min, the mixture was recooled to -78°C, diluted with dichloromethane (3 mL), and quenched by the successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.054 g, 0.12 mmol, 92% yield). ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm 9.86 (br s, 1H), 9.74 (s, 1H), 6.60 (s, 1H), 4.57 (br s, 1H), 4.20 (br s, 1H), 3.96 (s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.80 (br s, 1H), 3.36 (br s, 1H), 3.18 (br s, 2H), 3.04 (br s, 2H), 2.87-2.71 (m, 2H), 2.19 (s, 3H), 2.10 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H); MS (ESI ⁺ ) m/z 452.0 [M+H] ⁺ .

Example 177C: 1-ethyl-4-(2-methoxyvinyl)-3,5-dimethyl-1H-pyrazole

[00714] (Methoxymethyl)triphenylphosphonium chloride (1.32 g, 3.84 mmol) and tetrahydrofuran (4.9 mL) were added to the flask. The flask was cooled to 0 °C, then potassium 2-methylpropan-2-olate (1.0 M in tetrahydrofuran) (3.6 mL, 3.6 mmol) was added. Fifteen minutes later, a solution of 1-ethyl-3,5-dimethyl-1 H -pyrazole-4-carbaldehyde (0.450 g, 2.96 mmol) in tetrahydrofuran (4.9 mL) was added. The resulting mixture was stirred at 0 °C for 1 hour and then at ambient temperature for 17 hours. The mixture was then poured into saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (4 x 25 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography [40 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound [62:38 ( E )-( Z )] (0.342 g, 1.90 mmol, 64% yield). Data for the ( E )-isomer: ¹ H NMR (400 MHz, _CDCl3 ) δ ppm. 6.56 (d, J = 13.1 Hz, 1H), 5.52 (d, J = 13.0 Hz, 1H), 4.08-3.96 (m, 2H), 3.65 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.36 (t, J = 7.3 Hz, 3H). Data for ( Z )-isomer: ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm. 5.99 (d, J = 6.7 Hz, 1H), 5.00 (d, J = 6.7 Hz, 1H), 4.08-3.96 (m, 2H), 3.66 (s, 3H), 2.18 (2 overlapping singlets, 6H), 1.36 (t, J = 7.3 Hz, 3H); MS (ESI ⁺ ) m/z 181.6 [M+H] ⁺ .

Example 177D: 2-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)acetaldehyde

[00715] To the vial were added 1-ethyl-4-(2-methoxyvinyl)-3,5-dimethyl- 1H- pyrazole (0.200 g, 1.11 mmol) and tetrahydrofuran (5.6 mL). The vial was cooled to 0 °C. The solution was treated with 6.0 M hydrochloric acid (5.6 mL, 33 mmol) and then the ice bath was removed. The vial was allowed to warm to ambient temperature and then heated to 50 °C. After 1 h, the vial was cooled to ambient temperature and the solution was transferred to a beaker containing saturated aqueous sodium bicarbonate (60 mL). The resulting mixture was stirred for 15 min and then extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography [12 g column, gradient 0-100% ethyl acetate in heptanes] to give the title compound (0.114 g, 0.686 mmol, 62% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.56 (t, J = 2.5 Hz, 1H), 4.03 (q, J = 7.3 Hz, 2H), 3.39 (d, J = 2.5 Hz, 2H), 2.17 (s, 3H), 2.15 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H); MS (ESI ⁺ ) m/z 167.2 [M+H] ⁺ .

Example 178: N -(2,2-dimethylpropyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 277)

Example 178A: 6-(benzyloxy)-N-(2,2-dimethylpropyl)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00716] The title compound was prepared from 2,2-dimethylpropan-1-amine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 505.2 [M+H] ⁺ .

Example 178B: N-(2,2-dimethylpropyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00717] The title compound was prepared from Example 178A above using the procedures described for Example 159B in 14% yield (over 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.10 (s, 1H), 6.56-6.47 (m, 2H), 4.39 (s, 2H), 3.94 (s, 2H), 3.53 (t, J = 5.8 Hz, 2H), 2.90 (d, J = 6.1 Hz, 2H), 2.66 (t, J = 5.7 Hz, 2H), 0.81 (s, 9H); MS (APCI ⁺ ) m/z 415.2 [M+H] ⁺ .

Example 179: 8-fluoro-6-hydroxy- N -(3-methoxypropyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 278)

Example 179A: 6-(benzyloxy)-8-fluoro-N-(3-methoxypropyl)-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00718] The title compound was prepared from 3-methoxypropan-1-amine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 507.2 [M+H] ⁺ .

Example 179B: 8-fluoro-6-hydroxy-N-(3-methoxypropyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00719] The title compound was prepared from Example 179A above using the procedures described for Example 159B in 13% yield (for 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.62 (t, J =5.4 Hz, 1H), 6.49 (s, 1H), 4.35 (s, 2H), 3.94 (s, 2H), 3.49 (t, J =5.8 Hz, 2H), 3.31 (k, J =6.4 Hz, 2H), 3.21 (s, 3H), 3.08 (k, J =6.6 Hz, 2H), 2.65 (t, J =5.8 Hz, 2H), 1.65 (p, J =6.6 Hz, 2H); MS (CIAD ⁺ ) m/z 417.2 [M+H] ⁺ .

Example 180: 8-fluoro-6-hydroxy- N -(3-methoxy-2,2-dimethylpropyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 279)

Example 180A: 6-(benzyloxy)-8-fluoro-N-(3-methoxy-2,2-dimethylpropyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00720] The title compound was prepared from 3-methoxy-2,2-dimethylpropan-1-amine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 535.2 [M+H] ⁺ .

Example 180B: 8-fluoro-6-hydroxy-N-(3-methoxy-2,2-dimethylpropyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00721] The title compound was prepared from Example 180A above using the procedures described for Example 159B in 7% yield (for 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.49 (s, 1H), 6.42 (t, J = 6.1 Hz, 1H), 4.38 (s, 2H), 3.94 (s, 2H), 3.51 (t, J = 5.7 Hz, 2H), 3.23 (s, 3H), 3.03 (s, 2H), 2.98 (d, J = 6.0 Hz, 2H), 2.66 (t, J = 5.7 Hz, 2H), 0.79 (s, 6H); MS (CIAD ⁺ ) m/z 445.3 [M+H] ⁺ .

Example 181: N -[2-(dimethylamino)ethyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 280)

Example 181A: 6-(benzyloxy)-N-[2-(dimethylamino)ethyl]-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00722] The title compound was prepared from N,N -dimethylethane-1,2-diamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 506.2 [M+H] ⁺ .

Example 181B: N-[2-(dimethylamino)ethyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00723] The title compound was prepared from Example 181A above using the procedures described for Example 159B in 8% yield (for 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.27 (s, 1H), 9.10 (s, 1H), 6.88 (m, 1H), 6.52 (s, 1H), 4.40 (s, 2H), 3.94 (s, 2H), 3.53 (t, J= 5.7 Hz, 2H), 3.39-3.34 (m, 2H), 3.08 (s, 2H), 2.76 (s, 6H), 2.69 (t, J =5.9 Hz, 2H); MS (CIAD ⁺ ) m/z 416.3 [M+H] ⁺ .

Example 182: 8-fluoro-6-hydroxy- N -[2-(1-methylcyclopropyl)ethyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 281)

Example 182A: 6-(benzyloxy)-8-fluoro-N-[2-(1-methylcyclopropyl)ethyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00724] The title compound was prepared from 2-(1-methylcyclopropyl)ethan-1-amine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 517.2 [M+H] ⁺ .

Example 182B: 8-fluoro-6-hydroxy-N-[2-(1-methylcyclopropyl)ethyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00725] The title compound was prepared from Example 182A above using the procedures described for Example 159B in 6% yield (for 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.56 (t, J = 5.5 Hz, 1H), 6.48 (s, 1H), 4.34 (s, 2H), 3.93 (s, 2H), 3.48 (t, J = 5.8 Hz, 2H), 3.14-3.07 (m, 2H), 2.64 (t, J = 5.7 Hz, 2H), 1.40-1.32 (m, 2H), 1.01 (s, 3H), 0.32-0.15 (m, 4H); MS (CIAD ⁺ ) m/z 427.3 [M+H] ⁺ .

Example 183: 8-fluoro-6-hydroxy- N -(2-methoxyethyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 282)

Example 183A: 6-(benzyloxy)-8-fluoro-N-(2-methoxyethyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00726] The title compound was prepared from 2-methoxyethane-1-amine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 493.1 [M+H] ⁺ .

Example 183B: 8-fluoro-6-hydroxy-N-(2-methoxyethyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00727] The title compound was prepared from Example 183A above using the procedures described for Example 159B in 12% yield (for 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.69 (t, J = 5.5 Hz, 1H), 6.49 (s, 1H), 4.35 (s, 2H), 3.94 (s, 2H), 3.50 (t, J = 5.8 Hz, 2H), 3.33 (s, 2H), 3.23 (s, 3H), 3.22-3.14 (m, 2H), 2.65 (t, J = 5.8 Hz, 2H); MS (CIAD ⁺ ) m/z 403.2 [M+H] ⁺ .

Example 184: 8-fluoro-6-hydroxy- N -[(oxetan-3-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 283)

Example 184A: 6-(benzyloxy)-8-fluoro-N-[(oxetan-3-yl)methyl]-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00728] The title compound was prepared from oxetan-3-ylmethanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 505.1 [M+H] ⁺ .

Example 184B: 8-fluoro-6-hydroxy-N-[(oxetan-3-yl)methyl]-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00729] The title compound was prepared from Example 184A above using the procedures described for Example 159B in 4% yield (for 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.54-9.31 (m, 2H), 4.93 (t, J =5.3 Hz, 1H), 4.67-4.58 (m, 1H), 4.49 (s, 2H), 4.42-4.30 (m, 1H), 3.94 (s, 2H), 3.69-3.57 (m, 2H), 3.47 (d, J =4.5 Hz, 2H), 3.21 (dd, J =12.6, 7.9 Hz, 1H), 2.91-2.77 (m, 2H), 2.31-2.18 (m, 1H); MS (CIAD ⁺ ) m/z 415.2 [M+H] ⁺ .

Example 185: 8-fluoro-6-hydroxy- N -(2-phenylethyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 284)

Example 185A: 6-(benzyloxy)-8-fluoro-N-(2-phenylethyl)-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00730] The title compound was prepared from 2-phenylethan-1-amine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 539.2 [M+H] ⁺ .

Example 185B: 8-fluoro-6-hydroxy-N-(2-phenylethyl)-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00731] The title compound was prepared from Example 185A above using the procedures described for Example 159B in 14% yield (for 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.31-7.22 (m, 2H), 7.22-7.13 (m, 3H), 6.76 (t, J =5.4 Hz, 1H), 6.49 (s, 1H), 4.35 (s, 2H), 3.95 (s, 2H), 3.49 (t, J =5.8 Hz, 2H), 3.24 (dd, J =8.4, 6.3 Hz, 2H), 2.73 (dd, J =8.7, 6.4 Hz, 2H), 2.64 (t, J =5.8 Hz, 2H); MS (CIAD ⁺ ) m/z 449.3 [M+H] ⁺ .

Example 186: N -[3-(dimethylamino)propyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 285)

Example 186A: 6-(benzyloxy)-N-[3-(dimethylamino)propyl]-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00732] The title compound was prepared from N,N -dimethylpropane-1,3-diamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 520.1 [M+H] ⁺ .

Example 186B: N-[3-(dimethylamino)propyl]-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00733] The title compound was prepared from Example 186A above using the procedures described for Example 159B in 4% yield (over 2 steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.55-6.43 (m, 1H), 4.20 (s, 2H), 3.94 (s, 2H), 3.39-3.35 (m, 2H), 3.22-3.14 (m, 2H), 2.86-2.78 (m, 8H), 2.75 (t, J = 6.0 Hz, 2H), 1.88-1.75 (m, 2H); MS (APCI ⁺ ) m/z 430.3 [M+H] ⁺ .

Example 187: 5-[2-(3-cyclohexylpropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 286)

Example 187A: 5-[6-(benzyloxy)-2-(3-cyclohexylpropyl)-8-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00734] Sodium triacetoxyborohydride (77.0 mg, 0.36 mmol, 1.2 equivalents) was added in one portion to a suspension of 3-cyclohexylpropionaldehyde (100 mg, 0.69 mmol, 2.3 equivalents), the product of Example 54A (nominal 0.30 mmol, 1 equivalent), and triethylamine (0.13 mL, 0.93 mmol, 3.1 equivalents) in acetonitrile (0.86 mL, 0.35 M) at 23 °C. The reaction mixture was stirred for 18 h at 23 °C. The product mixture was sequentially diluted with saturated aqueous ammonium chloride (0.5 mL), water (0.5 mL), and dimethyl sulfoxide (1.0 mL). The diluted mixture was purified by reversed-phase flash column chromatography (50 g RediSep Rf Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to afford the title compound (134 mg, 0.25 mmol, 84% yield). MS (APCI ⁺ ) m/z 516 [M+H] ⁺ .

Example 187B: 5-[2-(3-cyclohexylpropyl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00735] A suspension of palladium on carbon (10 wt %, 27 mg, 0.025 mmol, 10 mol %), ammonium formate (79 mg, 1.26 mmol, 5 equivalents), and the product of Example 187A (134 mg, 0.25 mmol, 1 equivalent) in ethanol (2.5 mL, 0.1 M) was stirred for 18 h at 23 °C. The product mixture was filtered through a pad of diatomaceous earth (1.0 cm x 0.5 cm). The filter cake was washed with methanol (3 x 1.0 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue was purified by reverse phase flash column chromatography (50 g RediSep Rf Gold ^® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol in 3 column volumes, flow rate = 60 mL/min) to afford the title compound (75 mg, 0.17 mmol, 67% yield). 1H NMR (400 MHz, DMSO- d 6) δ ppm. 9.67 (s, 1H), 6.58 (s, 1H), 4.54-4.06 (m, 2H), 3.94 (s, 2H), 3.82-3.48 (m, 1H), 3.25-2.91 (m, 5H), 1.87-1.56 (m, 7H), 1.32-1.04 (m, 6H), 0.95-0.82 (m, 2H); MS (CIAD ⁺ ) m/z 467 [M+H+CH3CN] ⁺ .

Example 188: 5-(7-{[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 287)

Example 188A: 5-[3-(benzyloxy)-7-{[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]amino}-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00736] To a vial containing the product of Example 67F (0.080 g, 0.20 mmol) were added 1,2-dichloroethane (0.99 mL) and (3,5-dimethylisoxazol-4-yl)methanamine (0.037 g, 0.30 mmol). The resulting mixture was stirred at ambient temperature. After 30 minutes, sodium triacetoxyhydroborate (0.105 g, 0.495 mmol) was added. After fourteen hours, the reaction mixture was diluted with acetonitrile (3 mL), saturated aqueous ammonium chloride (3 mL), and water (3 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound as an ammonium salt (0.082 g, 0.16 mmol, 78% yield). ¹ H NMR (600 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.47 (d, J =7.1 Hz, 2H), 7.36-7.31 (m, 2H), 7.30-7.26 (m, 1H), 6.76 (s, 1H), 5.10 (s, 2H), 4.10 (s, 2H), 3.98 (dd, J =15.8, 13.8 Hz, 2H), 3.54 (tdd, J =10.6, 8.6, 5.5, 3.0 Hz, 1H), 3.25 (dd, J =16.1, 5.5 Hz, 1H), 2.88 (ddd, J =17.5, 5.2, 3.4 Hz, 1H), 2.80 (ddd, J =17.2, 11.5, 5.4 Hz, 1H), 2.69 (dd, J =16.0, 10.4 Hz, 1H), 2.45 (s, 3H), 2.35-2.31 (m, 1H), 2.29 (s, 3H), 1.80 (cd, J =12.0, 5.3 Hz, 1H); MS (ESI ⁺ ) m/z 515.0 [M+H] ⁺ .

Example 188B: 5-(7-{[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00737] A vial containing a suspension of 5-[3-(benzyloxy)-7-{[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]amino}-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione ammonium salt (0.079 g, 0.15 mmol) and 1,2,3,4,5-pentamethylbenzene (0.066 g, 0.44 mmol) in dichloromethane (1.5 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.2 mL, 1.2 mmol) was then added. The resulting mixture was stirred at -78°C for 10 min, then the dry ice-acetone bath was replaced with an ice-water bath. After 60 min, the mixture was recooled to -78°C, diluted with dichloromethane (3 mL), and quenched by successive additions of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.046 g, 0.11 mmol, 73% yield). ¹ H NMR (500 MHz, DMSO -d ₆ -D ₂ O) δ ppm 6.49 (s, 1H), 4.08 (s, 2H), 3.99 (dd, J =15.9, 13.8 Hz, 2H), 3.51 (ddt, J =14.3, 10.5, 4.4 Hz, 1H), 3.19 (dd, J =15.9, 5.5 Hz, 1H), 2.87-2.70 (m, 2H), 2.56 (dd, J = 15.9, 10.3 Hz, 1H), 2.41 (s, 3H), 2.28 (br s, 1H), 2.27 (s, 3H), 1.72 (cd, J = 11.8, 5.5 Hz, 1H); MS (ESI ⁺ ) m/z 424.8 [M+H] ⁺ .

Example 189: 5-{2-[3-(2,2-dimethylcyclopropyl)propyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 288)

Example 189A: tert-butyl 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00738] A suspension of the product of Example 44H (150 mg, 0.31 mmol, 1 equivalent), palladium on carbon (33 mg, 0.03 mmol, 10 mol %), and ammonium formate (58 mg, 0.92 mmol, 3.0 equivalents) in ethanol (1.5 mL, 0.2 M) was sealed in a 20 mL scintillation pressure release vial fitted with a screw cap with a septum. The sealed reaction vessel was placed in a heating block preheated to 50 °C. The reaction mixture was stirred for 1 h at 50 °C. The product mixture was cooled to 23 °C. The cooled mixture was filtered through a pad of diatomaceous earth (1.0 cm x 0.5 cm). The filter cake was washed with methanol (3 x 3.0 mL). The filtrates were combined and the combined filtrates were concentrated. The resulting residue was used without further purification in the next step. MS (APCI ⁺ ) m/z 419 [M+NH ₄ ] ⁺ .

Example 189B: 5-(8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione trifluoroacetate

[00739] Trifluoroacetic acid (0.35 mL, 4.58 mmol, 15.0 equivalents) was added to a suspension of the product from Example 189A (nominally 0.31 mmol, 1 equivalent) in dichloromethane (1.5 mL, 0.2 M) at 23 °C. The reaction mixture was stirred for 1 h at 23 °C. The product mixture was diluted with ether (5.0 mL) and acetonitrile (2.0 mL). The mixture was concentrated. The resulting residue was re-concentrated from 20% acetonitrile ether (v/v, 5.0 mL). The residue of the resulting title compound was dried under vacuum for 18 h at 23 °C (137 mg) and used without further purification in the next step. 1H NMR (500 MHz, DMSO -d 6) δ ppm 9.26 (s, 2H), 6.59 (s, 1H), 4.15 (s, 2H), 4.09 (s, 2H), 3.33 (br, 2H), 2.92 (t, J =6.21 Hz, 2H).

Example 189C: 5-{2-[3-(2,2-dimethylcyclopropyl)propyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

[00740] Dess-Martin periodinane (331.0 mg, 0.78 mmol, 2.6 equivalents) was added to a solution of 3-(2,2-dimethylcyclopropyl)propanol (100.0 mg, 0.78 mmol, 2.6 equivalents) in dichloromethane (3.90 mL) at 23 °C. The reaction mixture was stirred for 20 min at 23 °C. The product mixture was then diluted with ether (10 mL). The diluted mixture was filtered through a diatomaceous earth plug (2.0 cm × 1.0 cm). The filter cake was washed with ether (3 × 2 mL). The filtrates were combined, and the combined filtrates were concentrated to a viscous suspension (~1 mL). Pentane (5 mL) was added to the mixture. The resulting suspension was filtered through a diatomaceous earth plug (1.0 cm × 0.5 cm). The filter cake was washed with pentane (3×1 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue, 3-(2,2-dimethylcyclopropyl)propanal, was added to a suspension of the product from Example 189B (nominally 0.31 mmol, 1 equivalent) and triethylamine (0.13 mL, 0.92 mmol, 3.0 equivalents) in acetonitrile (3.0 mL, 0.1 M) at 23 °C. The reaction mixture was stirred for 2 min at 23 °C. Sodium triacetoxyborohydride (78 mg, 0.37 mmol, 1.2 equivalents) was added in one portion at 23 °C. The reaction mixture was stirred for 30 min at 23 °C. The product mixture was diluted with water (0.5 mL). The diluted product mixture was concentrated to a volume of ~1 mL. The concentrated mixture was diluted with dimethyl sulfoxide (2 mL). The diluted mixture was purified by reverse phase flash column chromatography (30 g RediSep Rf Gold ^® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol in 3 column volumes, flow rate = 40 mL/min) to give the title compound (98 mg, 0.24 mmol, 75% over three steps). 1H NMR (500 MHz, DMSO- d 6) δ ppm. 9.69 (s, 1H), 9.63 (br, 1H), 6.58 (s, 1H), 4.57-4.04 (m, 1H), 3.94 (s, 2H), 3.67 (br, 1H), 3.23 (br, 2H), 3.00 (br, 2H), 1.80 (g, J =7.6 Hz, 1H), 1.40 (dk, J =14.4, 7.2 Hz, 1H), 1.29 (dk, J =14.6, 7.5 Hz, 1H), 1.04 (s, 3H), 1.03 (s, 3H), 0.52 (dtd, J =8.6, 7.2, 5.2 Hz, 1H), 0.39 (dd, J =8.5, 4.0 Hz, 1H), -0.05 (dd, J =5.3, 3.9 Hz, 1H); MS (CIAD ⁺ ) m/z 412 [M+H] ⁺ .

Example 190: 5-[(3 S )-5-fluoro-7-hydroxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 289)

Example 190A: tert-butyl {(2S)-1-[4-(benzyloxy)-6-bromo-2-fluoro-3-(2,2,2-trifluoroacetamido)phenyl]propan-2-yl}carbamate

[00741] A solution of n -butyl lithium in hexane (2.44 M, 6.90 mL, 16.83 mmol, 2.2 equivalents) was added to a solution of diisopropylamine (2.62 mL, 18.36 mmol, 2.4 equivalents) in tetrahydrofuran (40 mL) at -76 °C (internal temperature). A slight exotherm was observed. The reaction mixture was stirred for 20 min until the internal temperature was restored to -76 °C. A solution of the product from Example 12C (3.00 g, 7.65 mmol, 1 equivalent) in tetrahydrofuran (15.0 mL) was added dropwise over 45 min such that the maximum observed internal temperature was <-72 °C (internal temperature). After complete addition, the reaction mixture was stirred for 30 min at <-72 °C (internal temperature). Then, a solution of ( S ) -tert -butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.36 g, 9.95 mmol, 1.3 equivalents) in tetrahydrofuran (15.0 mL) was added dropwise over 45 min such that the maximum internal temperature observed during the addition was <-72 °C. After complete addition, the reaction mixture was stirred for 30 min at <-72 °C (internal temperature). Then, aqueous hydrogen chloride solution (1.0 M, 10.0 mL, 1.3 equivalents) was added at -76 °C (internal temperature). The reaction vessel was immediately removed from the cooling bath and allowed to warm to ~23 °C over 30 min. Additional aqueous hydrogen chloride solution (1.0 M, 25.0 mL, 3.27 equivalents) was added at 23 °C. The reaction mixture was stirred for 25 min at 23 °C. The product mixture was then partitioned between ethyl acetate (200 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, and the combined organic layers were washed successively with saturated aqueous ammonium bisulfate solution (50 mL) and saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The resulting residue was dissolved in a mixture of 10% acetone-20% ethyl acetate-ether (v/v/v, 30 mL). Diatomaceous earth (5 g) was added to the solution, and the mixture was concentrated. The resulting residue was purified by flash column chromatography (40 g RediSep Rf Gold ^® silica gel column, elution with a gradient of 0-100% [v/v] ethyl acetate - heptanes). The fractions containing the product were collected and the combined fractions were concentrated. The title compound thus obtained was used without further purification in the next step. MS (APCI ⁺ ) m/z 449 [MS(O)OC(CH ₃ ) ₃ +H] ⁺ .

Example 190B: methyl {[6-(benzyloxy)-4-bromo-3-{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}-2-fluorophenyl](trifluoroacetyl)amino}acetate

[00742] Methyl bromoacetate (0.78 mL, 8.42 mmol, 1.1 equivalents) was added to a suspension of the product from Example 190A (nominal 7.65 mmol, 1 equivalent), cesium carbonate (2.12 g, 15.30 mmol, 2.0 equivalents), and potassium iodide (1.27 g, 7.65 mmol, 1.0 equivalents) in acetone (40 mL, 0.2 M) at 23 °C. The reaction mixture was stirred for 23 h at 23 °C. The reaction vessel was sealed with a reflux condenser, and the sealed reaction vessel was placed on a heating block preheated to 60 °C. The reaction mixture was stirred for 3 h at 60 °C. The product mixture was then concentrated under a stream of nitrogen to a viscous suspension (~10 mL). The suspension was partitioned between ethyl acetate (75 mL) and saturated aqueous ammonium chloride solution (30 mL). The aqueous layer was extracted with ethyl acetate (25 mL). The organic layers were combined, and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (~10 g) was added to the filtrate, and the mixture was concentrated. The resulting residue was purified by flash column chromatography (RediSep Rf ^Gold® silica gel column 80 g, eluting with a gradient of 0-100% [v/v] ethyl acetate - heptanes) to afford the title compound (2.68 g, 4.31 mmol, 56% yield). MS (CIAD ⁺ ) m/z 621 [M+H] ⁺ .

Example 190C: methyl {[6-(benzyloxy)-3-{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}-4-ethenyl-2-fluorophenyl](trifluoroacetyl)amino}acetate

[00743] A suspension of cesium carbonate (2.12 g, 6.50 mmol, 2.0 equivalents), potassium vinyl trifluoroborate (871 mg, 6.50 mmol, 2.0 equivalents), bis(triphenylphosphine) palladium(II) dichloride (114 mg, 0.16 mmol, 5.0 mol %), and the product from Example 190B (nominal 2.02 g, 3.25 mmol, 1 equivalent) in 20% aqueous dioxane (v/v, 32.5 mL, 0.1 M) in a 100 mL round-bottomed flask was fitted with a reflux condenser and sealed with a rubber septum. The sealed reaction mixture was deoxygenated by repeated evacuation (~5 sec) and subsequent flushing with nitrogen (×2). The reaction vessel was placed in a heating block preheated to 80 °C. The reaction mixture was stirred for 1 h at 80 °C. The product mixture was then cooled to 23 °C. The cooled product mixture was filtered through a pad of diatomaceous earth (3.0 cm × 1.0 cm). The filter cake was washed with ethyl acetate (3 × 15 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue was partitioned between ethyl acetate (50 mL) and water (10 mL). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (~5 g) was added to the solution, and the mixture was concentrated. The resulting residue was purified by flash column chromatography (RediSep Rf Gold ^® 80 g silica gel column, eluting with a gradient of 0-100% [v/v] ethyl acetate-heptanes). Fractions containing the title compound were collected and concentrated. The resulting title compound (1.62 g, <88% yield) was used without further purification in the next step. MS (APCI ⁺ ) m/z 469 [MS(O)OC(CH ₃ ) ₃ +H] ⁺ .

Example 190D: methyl {[6-(benzyloxy)-3-{(2S)-2-[(tert-butoxycarbonyl)amino]propyl}-2-fluoro-4-formylphenyl](trifluoroacetyl)amino}acetate

[00744] A solution of N -methylmorpholine N -oxide in water (50% w/v, 2.00 mL, 8.55 mmol, 3.0 equivalents) was added to a suspension of potassium osmate dihydrate (42 mg, 0.14 mmol, 4.0 mol %) and the product from Example 190C (nominal 1.62 g, 2.85 mmol, 1 equivalent) in 25% water-tetrahydrofuran (v/v, 28 mL, 0.1 M) at 23 °C. The reaction mixture was stirred for 18 h at 23 °C. Sodium metaperiodate (1.83 g, 8.55 mmol, 3.0 equivalents) was added in one portion at 23 °C. The reaction mixture was stirred for 3 h at 23 °C. The product mixture was successively diluted with saturated aqueous sodium thiosulfate solution (15 mL), water (10 mL), and ethyl acetate (75 mL). The diluted mixture was stirred for 20 min at 23 °C. The resulting two-phase mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (25 mL). The organic layers were combined, and the combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (~10 g) was added to the filtrate, and the mixture was concentrated. The resulting residue was purified by flash column chromatography (RediSep Rf ^Gold® 120 g silica gel column, eluting with a gradient of 0-100% [v/v] ethyl acetate - heptanes) to give the title compound (410 mg, 0.71 mmol, 25% yield). MS (APCI ⁺ ) m/z 471 [MC(O)OC(CH ₃ ) ₃ +H] ⁺ .

Example 190E: tert-butyl (3S)-7-(benzyloxy)-5-fluoro-6-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00745] Triethylsilane (0.38 mL, 2.36 mmol, 3.5 equivalents) and boron trifluoride diethyl etherate (0.26 mL, 2.02 mmol, 3.0 equivalents) were added dropwise sequentially to a solution of the product from Example 190D (385.0 mg, 0.68 mmol, 1 equivalent) in dichloromethane (7.0 mL) at a rate such that the internal temperature did not exceed -77 °C. The reaction mixture was stirred for 1 h at an internal temperature of <-75 °C. Additional triethylsilane (0.10 mL, 0.63 mmol, 0.92 equivalents) was added at a rate such that the internal temperature did not exceed -75 °C. The reaction mixture was stirred for 20 min at an internal temperature of <-75 °C. Additional boron trifluoride diethyl etherate (0.26 mL, 2.02 mmol, 0.75 equivalents) was added such that the internal temperature did not exceed -75 °C. The reaction mixture was stirred for 20 min at an internal temperature of <-75 °C. Additional triethylsilane (0.10 mL, 0.63 mmol, 0.92 equivalents) and boron trifluoride diethyl etherate (0.26 mL, 2.02 mmol, 0.75 equivalents) were added sequentially such that the internal temperature did not exceed -75 °C. The reaction mixture was stirred for 20 min at an internal temperature of <-75 °C. The product mixture was then diluted sequentially with saturated aqueous sodium bicarbonate (2 mL), water (1 mL), and ethyl acetate (25 mL), and the diluted mixture was allowed to warm to 23 °C over 16 h. The heated mixture was partitioned between water (2 mL) and ethyl acetate (15 mL). The organic layer was washed with saturated aqueous sodium chloride solution (2 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was dissolved in ~10% toluene-heptanes (v/v, 8 mL) and the solution was purified by flash column chromatography (40 g RediSep Rf Gold ^® silica gel column, eluting with a gradient of 0-100% [v/v] ethyl acetate-heptanes) to afford the title compound (307 mg, 0.543 mmol, 82% yield). MS (APCI ⁺ ) m/z 612 [M + CH3N + H] ⁺ .

190F: tert-butyl (3S)-7-(benzyloxy)-5-fluoro-6-[(2-methoxy-2-oxoethyl)amino]-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00746] A solution of sodium methoxide in methanol (0.5 M, 2.77 mL, 1.38 mmol, 2.5 equivalents) was added to a solution of the product from Example 190E (307 mg, 0.55 mmol, 1 equivalent) in anhydrous methanol (2.8 mL, 0.2 M) in a sealed reaction vessel under nitrogen at 23 °C. The reaction vessel was placed on a heating block preheated to 50 °C. The reaction mixture was stirred for 30 min at 50 °C. The reaction mixture was cooled to 23 °C. The cooled mixture was diluted with saturated aqueous ammonium chloride (3 mL). The diluted mixture was concentrated under a stream of nitrogen. The resulting residue was partitioned between ethyl acetate (25 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layers were combined, and the combined organic layers were washed successively with saturated aqueous sodium bicarbonate solution (10 mL) and saturated aqueous sodium chloride solution (5 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The resulting title compound was used without further purification in the next step. MS (APCI ⁺ ) m/z 459 [M+H] ⁺ .

Example 190G: tert-Butyl (3S)-7-(benzyloxy)-5-fluoro-6-[(2-methoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00747] Allyl alcohol (0.04 mL, 0.61 mmol, 1.1 equivalents) was added to a solution of chlorosulfonyl isocyanate (0.05 mL, 0.61 mmol, 1.1 equivalents) in dichloromethane (2.8 mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. A solution of the product from Example 190F (nominally 0.55 mmol, 1 equivalent) and N,N -diisopropylethylamine (0.19 mL, 1.11 mmol, 2.0 equivalents) in dichloromethane (2.8 mL, total 0.1 M) was added dropwise over 3 min at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. The product mixture was diluted with water (5 mL). The resulting biphasic mixture was stirred for 30 min. The mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (2×10 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (5 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting title compound was used without further purification in the next step. MS (APCI ⁺ ) m/z 639 [M+NH4] ⁺ .

Example 190H: tert-butyl (3S)-7-(benzyloxy)-5-fluoro-3-methyl-6-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00748] A solution of sodium methoxide in methanol (0.5 M, 3.32 mL, 1.66 mmol, 3.0 equivalents) was added to a suspension of the product from Example 190G (nominally 0.554 mmol, 1 equivalent) and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol, 0.05 equivalents) in methanol (3.0 mL, 0.19 M) under nitrogen at 23 °C. The reaction vessel was placed in a heating block preheated to 60 °C. The reaction mixture was stirred for 10 min at 60 °C. The product mixture was then cooled to 23 °C. The cooled mixture was diluted with saturated aqueous ammonium chloride (3.0 mL). The diluted mixture was partially concentrated. The resulting residue was suspended in dimethyl sulfoxide (10 mL) and water (3 mL). The diluted mixture was purified by reverse phase flash column chromatography (100 g RediSep Rf Gold® C18 column, eluting with a gradient of 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol in 3 column volumes, flow rate = 80 mL/min) to give the title compound (65 mg, 0.13 mmol, 23% over three steps). MS ( ^APCI ) m/z 523 [M+NH4] ⁺ .

Example 190I: tert-butyl (3S)-5-fluoro-7-hydroxy-3-methyl-6-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate, ammonium salt

[00749] A suspension of the product from Example 190H (65 mg, 0.13 mmol, 1 equivalent), palladium on carbon (14 mg, 0.01 mmol, 0.1 equivalent), and ammonium formate (20 mg, 0.32 mmol, 2.5 equivalents) in ethanol (1.3 mL, 0.1 M) was sealed in a 20 mL scintillation pressure release vial fitted with a screw cap with a septum. The sealed reaction vessel was placed in a heating block preheated to 50 °C. The reaction mixture was stirred for 30 min at 50 °C. The product mixture was cooled to 23 °C. The cooled mixture was filtered through a pad of diatomaceous earth (1.0 cm x 0.5 cm). The filter cake was washed with methanol (3 x 1.0 mL). The filtrates were combined and the combined filtrates were concentrated. The resulting residue was dissolved in 50% aqueous dimethyl sulfoxide (v/v, 6 mL). The solution was purified by reverse phase flash column chromatography (30 g RediSep Rf ^Gold® C18 column, eluting with a gradient of 5-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate = 35 mL/min) to give the title compound (22.5 mg, 0.050 mmol, 41% yield). MS ( ^APCI ) m/z 433 [M+NH4] ⁺ .

Example 190J: 5-[(3S)-5-fluoro-7-hydroxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, hydrochloride salt

[00750] A solution of hydrogen chloride in dioxane (4.0 M, 0.14 mL, 0.56 mmol, 10.8 equivalents) was added to the product from Example 190J (22.5 mg, 0.05 mmol, 1 equivalent) at 23 °C. The reaction mixture was stirred for 30 min at 23 °C. The product mixture was concentrated under a stream of nitrogen to give the title compound (hydrochloride salt) with one equivalent of ammonium chloride as excipient (16.9 mg, 0.046 mmol, 88% yield). 1H NMR (400 MHz, DMSO -d 6) δ ppm 10.49 (br, 1H), 9.78 (br, 1H), 9.47 (br, 1H), 7.27 (apparent triplet, 3×NH, 3H), 6.67 (s, 1H), 4.34 (s, 2H), 4.30-4.17 (m, 2H), 3.52-3.39 (m, 2H), 2.96 (dd, J = 16.8, 4.6 Hz, 1H), 2.57 (dd, J = 17.1, 10.8 Hz, 1H), 1.40 (d, J = 6.4 Hz, 3H); MS (APCI ⁺ ) m/z 316 [M+H] ⁺ . =

Example 191: 5-(7-{[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 290)

Example 191A: 5-[3-(benzyloxy)-7-{[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]amino}-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00751] To a vial containing the product from Example 67F (0.080 g, 0.20 mmol) were added 1,2-dichloroethane (0.99 mL) and 2-(3,5-dimethylisoxazol-4-yl)ethan-1-amine (0.042 g, 0.30 mmol). The resulting mixture was stirred at ambient temperature. After 30 minutes, sodium triacetoxyhydroborate (0.105 g, 0.495 mmol) was added. After fourteen hours, the reaction mixture was diluted with acetonitrile (3 mL), saturated aqueous ammonium chloride (3 mL), and water (3 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g sphere column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.077 g, 0.15 mmol, 74% yield). ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm 8.70 (b, s, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.31-7.25 (m, 1H), 6.75 (s, 1H), 5.11 (s, 2H), 3.97 (dd, J = 17.4, 13.4 Hz, 2H), 3.51 (lat s, 1H), 3.20-3.07 (m, 3H), 2.91-2.72 (m, 2H), 2.68 (dd, J =8.4, 6.9 Hz, 2H), 2.62 (dd, J =16.3, 9.6 Hz, 1H), 2.35 (s, 3H), 2.21 (s, 3H), 2.19 (br s, 1H), 1.74 (cd, J =11.4, 5.3 Hz, 1H); MS (ESI ⁺ ) m/z 529.0 [M+H] ⁺ .

Example 191B: 5-(7-{[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00752] A vial containing a suspension of 5-[3-(benzyloxy)-7-{[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]amino}-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.072 g, 0.14 mmol) and 1,2,3,4,5-pentamethylbenzene (0.060 g, 0.41 mmol) in dichloromethane (1.4 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.1 mL, 1.1 mmol) was then added. The resulting mixture was stirred at -78°C for 10 min, then the dry ice-acetone bath was replaced with an ice-water bath. After 60 min, the mixture was recooled to -78°C, diluted with dichloromethane (3 mL), and quenched by the successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was then allowed to warm to ambient temperature and stirred for 15 min. The mixture was concentrated under reduced pressure and then co-evaporated with ethanol (2 x 5 mL). The residue was purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 40-60 μm, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.049 g, 0.11 mmol, 83% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.29 (lat s, 1H), 8.65 (lat s, 2H), 6.48 (s, 1H), 3.95 (dd, J =15.9, 13.4 Hz, 2H), 3.53-3.44 (m, 1H), 3.15-3.07 (m, 3H), 2.82 (dt, J =17.3, 4.8 Hz, 1H), 2.74 (dd, J =11.7, 11.2, 4.9 Hz, 1H), 2.67 (dd, J =9.6, 6.6 Hz, 2H), 2.56 (dd, J =16.1, 9.8 Hz, 1H), 2.35 (s, 3H), 2.21 (s, 3H), 2.19-2.15 (m, 1H), 1.78-1.65 (m, 1H); MS (ESI ⁺ ) m/z 439.1 [M+H] ⁺ .

Example 192: 5-[(2 R )-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1 H -inden-5-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 291)

[00753] The product of Example 169 was separated by preparative chiral SFC. Preparative SFC was performed on a Waters SFC 80Q system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 delivered via a dry non-certified _CO2 Dewar at 350 psi with a methanol modifier (0.1% trifluoroacetic acid:triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 120 bar. The sample was dissolved in 1:4 methanol:dichloromethane at a concentration of 4 mg/mL. The sample was loaded into the modifier stream in 2 mL injections. The mobile phase was maintained isocratically at 40% cosolvent:CO ₂ . The instrument was equipped with a CHIRALPAK® IC column with a 30 mm × 250 mm i.d. and 5 μm particles. The enantiomer peak eluted early to give the title compound (14 mg, 0.036 mmol, 38.4% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm (J = 7.6, Hz, 10.3, CHCl 2 ) was found to be between 1.5 and 1.5 °C. 6.57 (s, 1H), 3.92 (s, 2H), 3.02-2.92 (m, 4H), 2.89-2.84 (m, 2H), 2.76 -2.79 (m, 1H), 2.68-2.61 (m, 2H), 1.62 (hept, J =6.7 Hz, 1H), 1.49-1.43 (m, 2H), 0.89 (d, J =6.7 Hz, 6H); MS (CIAD ⁺ ) m/z 386 [M+H] ⁺ .

Example 193: 5-[(2 S )-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1 H -inden-5-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 292)

[00754] The product of Example 169 was separated by preparative chiral SFC. Preparative SFC was performed on a Waters SFC 80Q system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 delivered via a dry non-certified _CO2 Dewar at 350 psi with a methanol modifier (0.1% trifluoroacetic acid:triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 120 bar. The sample was dissolved in 1:4 methanol:dichloromethane at a concentration of 4 mg/mL. The sample was loaded into the modifier stream in 2 mL injections. The mobile phase was maintained isocratically at 40% cosolvent:CO ₂ . The instrument was equipped with a CHIRALPAK® IC column with a 30 mm × 250 mm i.d. and 5 μm particles. The late eluting enantiomer peak gave the title compound (9.5 mg, 0.025 mmol, 26% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 6.58 (s, 1H), 3.93 (s, 2H), 3.04-2.96 (m, 4H), 2.93-2.87 (m, 2H), 2.78-2.70 (m, 1H), 2.68-2.62 (m, 2H), 1.62 (hept, J =6.6 Hz, 1H), 1.51-1.44 (m, 2H), 0.89 (d, J =6.6 Hz, 6H); MS (CIAD ⁺ ) m/z 386 [M+H] ⁺ .

Example 194: 5-[8-fluoro-6-hydroxy-2-(4-methoxybutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 293)

Example 194A: 5-(8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione hydrochloride (Alternative preparation Example 44I)

[00755] A solution of hydrogen chloride in dioxane (4.0 M, 1.25 mL, 4.98 mmol, 4.8 equivalents) was added to a suspension of the product from Example 189A (nominal 1.04 mmol, 1 equivalent) in dioxane (4.15 mL, 0.25 M) at 23 °C. The reaction mixture was stirred for 2 hours at 23 °C. The mixture was diluted with ether (3.0 mL), and the diluted mixture was concentrated. The resulting residue was dried for 18 hours in a vacuum oven at 50 °C. To the residue obtained at 23 °C was added additional hydrogen chloride in dioxane (4.0 M, 3.0 mL, 12.00 mmol, 11.5 equivalents). The reaction mixture was stirred for 18 hours at 23 °C. The reaction mixture was diluted with ether (3.0 mL) and the diluted mixture was concentrated. The resulting residue was dried for 6 h in a vacuum oven at 50 °C to give the title compound. 1H NMR (500 MHz, DMSO -d 6) δ ppm 10.28 (br, 1H), 9.40 (br, 1H), 6.62 (s, 1H), 4.22 (s, 2H), 4.13 (s, 2H), 3.34-3.28 (m, 2), 2.93 (t, J = 6.2 Hz, 2H); MS ( ^APCI ) m/z 316 [M+H] ⁺ .

Example 194B: 5-[8-fluoro-6-hydroxy-2-(4-methoxybutyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00756] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 4-Methoxybutanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC on a Waters XBridge™ C8 5 µm column (75 mm x 30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used at a flow rate of 40 mL/min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (6.8 mg, 0.018 mmol, 30% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.44 (s, 1H), 3.93 (s, 2H), 3.41 (s, 2H), 3.25-3.19 (m, 5H), 2.71 (t, J =5.7 Hz, 2H), 2.60 (t, J =5.8 Hz, 2H), 2.50-2.45 (m, 2H), 1.57-1.47 (m, 4H); MS (CIAD ⁺ ) m/z 388 [M+H] ⁺ .

Example 195: 5-(8-fluoro-6-hydroxy-2-{3-[3-(trifluoromethyl)phenyl]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 294)

[00757] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalents) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 3-(3-(Trifluoromethyl)phenyl)propanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm x 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to afford the title compound (9.3 mg, 0.019 mmol, 32% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 7.61-7.47 (m, 3H), 6.45 (s, 1H), 3.93 (s, 2H), 3.41 (s, 3H), 2.77-2.68 (m, 4H), 2.59 (t, J =5.8 Hz, 2H), 2.47 (t, J =7.0 Hz, 2H), 1.84 (p, J =7.2 Hz, 2H); MS (CIAD ⁺ ) m/z 488 [M+H] ⁺ .

Example 196: 5-(8-fluoro-6-hydroxy-2-{2-methyl-3-[4-(propan-2-yl)phenyl]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 295)

[00758] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 3-(4-Isopropylphenyl)-2-methylpropanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm × 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min, linear gradient 100-15% A, 9.1-10.0 min 15% A) to afford the title compound (2 mg, 0.0042 mmol, 7% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 7.14 (d, J =8.0 Hz, 2H), 7.08 (d, J =7.9 Hz, 2H), 6.44 (s, 1H), 3.93 (s, 2H), 3.40 (s, 3H), 2.84 (p, J =6.9 Hz, 1H), 2.74-2.68 (m, 2H), 2.62-2.57 (m, 2H), 2.39-2.22 (m, 3H), 2.10-1.94 (m, 1H), 1.18 (d, J =6.9 Hz, 6H), 0.80 (d, J =6.5 Hz, 3H); MS (CIAD ⁺ ) m/z 476 [M+H] ⁺ .

Example 197: 5-{2-[4-(5,5-dimethyl-1,3-dioxan-2-yl)butyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 296)

[00759] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 4-(5,5-Dimethyl-1,3-dioxan-2-yl)butanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm × 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to afford the title compound (9.4 mg, 0.020 mmol, 34% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 9.24 (s, 1H), 7.13 (s, 1H), 6.49 (s, 1H), 4.42 (t, J =4.9 Hz, 1H), 3.93 (s, 2H), 3.54-3.47 (m, 4H), 3.41-3.34 (m, 4H), 2.94-2.63 (m, 4H), 1.66-1.51 (m, 4H), 1.44-1.32 (m, 2H), 1.07 (s, 3H), 0.67 (s, 3H); MS (CIAD ⁺ ) m/z 472 [M+H] ⁺ .

Example 198: 5-{8-fluoro-6-hydroxy-2-[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 297)

[00760] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 2-(2,6,6-Trimethylcyclohex-1-en-1-yl)acetaldehyde (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm × 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-15% A, 9.1-10.0 min 15% A) to afford the title compound (8.2 mg, 0.018 mmol, 31% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 6.45 (s, 1H), 3.93 (s, 2H), 3.52-3.48 (m, 2H), 3.32-3.28 (m, 2H), 2.84-2.61 (m, 4H), 2.29-2.20 (m, 2H), 1.96-1.85 (m, 2H), 1.61 (s, 3H), 1.57-1.48 (m, 2H), 1.43-1.35 (m, 2H), 0.99 (s, 6H); MS (CIAD ⁺ ) m/z 452 [M+H] ⁺ .

Example 199: 5-(8-fluoro-6-hydroxy-2-pentyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 298)

[00761] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). Pentanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated, and the residue was purified by reversed phase preparative HPLC on a Waters XBridge™ C8 5 µm column (75 mm x 30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used at a flow rate of 40 mL/min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (6 mg, 0.016 mmol, 27% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.36 (s, 1H), 7.10 (s, 1H), 6.51 (s, 1H), 3.96-3.54 (m, 4H), 3.17-2.62 (m, 6H), 1.71-1.53 (m, 2H), 1.38-1.23 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H); MS (CIAD ⁺ ) m/z 372 [M+H] ⁺ .

Example 200: 5-{8-fluoro-2-[3-(4-fluorophenyl)propyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 299)

[00762] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 3-(4-Fluorophenyl)propanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm × 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-15% A, 9.1-10.0 min 15% A) to afford the title compound (8.9 mg, 0.020 mmol, 34% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 7.29-7.21 (m, 2H), 7.14-7.03 (m, 2H), 6.44 (s, 1H), 3.93 (s, 2H), 3.41 (s, 2H), 2.71 (t, J =5.8 Hz, 2H), 2.65-2.56 (m, 4H), 2.46 (t, J =7.1 Hz, 2H), 1.79 (p, J =7.4 Hz, 2H); MS (CIAD ⁺ ) m/z 438 [M+H] ⁺ .

Example 201: tert -butyl [(1 r ,4 r )-4-{2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinolin-2(1 H )-yl]ethyl}cyclohexyl]carbamate (Compound 300)

[00763] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). tert -Butyl [(1 r ,4 r )-4-(2-oxoethyl)cyclohexyl]carbamate (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm × 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-15% A, 9.1-10.0 min 15% A) to afford the title compound (12.5 mg, 0.024 mmol, 40% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 9.23 (s, 1H), 7.12 (s, 1H), 6.65 (d, J =8.1 Hz, 1H), 6.48 (s, 1H), 3.93 (s, 2H), 3.83-3.47 (m, 2H), 3.22-3.05 (m, 2H), 2.79 (s, 4H), 1.80-1.66 (m, 5H), 1.46 (s, 2H), 1.39-1.34 (m, 10H), 1.18-1.05 (m, 2H), 0.95 (td, J = 14.1, 13.4, 7.3 Hz, 2H); MS (CIAD ⁺ ) m/z 527 [M+H] ⁺ .

Example 202: 5-{2-[3-(4- tert -butylphenyl)propyl]-8-fluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 301)

[00764] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 3-(4-( tert -Butyl)phenyl)propanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm × 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-15% A, 9.1-10.0 min 15% A) to afford the title compound (8 mg, 0.017 mmol, 28% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 7.32-7.25 (m, 2H), 7.17-7.10 (m, 2H), 6.44 (s, 1H), 3.93 (s, 2H), 3.41 (s, 2H), 2.71 (t, J =5.7 Hz, 2H), 2.63-2.52 (m, 4H), 2.47 (d, J =7.2 Hz, 2H), 1.85-1.73 (m, 2H), 1.26 (s, 9H); MS (CIAD ⁺ ) m/z 476 [M+H] ⁺ .

Example 203: 5-[8-fluoro-6-hydroxy-2-(3,5,5-trimethylhexyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 302)

[00765] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 3,5,5-Trimethylhexanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm × 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-15% A, 9.1-10.0 min 15% A) to afford the title compound (7.8 mg, 0.018 mmol, 31% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 9.21 (s, 1H), 7.10 (s, 1H), 6.48 (s, 1H), 3.93 (s, 2H), 3.85-3.42 (m, 2H), 3.05-2.54 (m, 6H), 1.59-1.49 (m, 2H), 1.49-1.34 (m, 1H), 1.25 (dd, J =13.9, 3.1 Hz, 1H), 1.05 (dd, J =14.0, 5.6 Hz, 1H), 0.93 (d, J =6.3 Hz, 3H), 0.89 (s, 9H); MS (CIAD ⁺ ) m/z 428 [M+H] ⁺ .

Example 204: 5-{8-fluoro-2-[3-(2-fluorophenyl)propyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 303)

[00766] The product from Example 194A (20 mg, 0.056 mmol, 1.0 equivalent) was dissolved in sodium acetate/acetic acid buffer (pH 4-5, 1.0 mL). 3-(2-Fluorophenyl)propanal (0.6 M in methanol, 246 µL, 0.15 mmol, 2.5 equivalents) was added at room temperature. Cyanoborohydride resin ( ^Biotage® MP-Cyanoborohydride, 2.28 mmol/g, 63 mg, 0.14 mmol, 2.5 equivalents) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated and the residue was purified by reversed-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm × 30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-15% A, 9.1-10.0 min 15% A) to afford the title compound (0.1 mg, 0.0002 mmol, 1% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 7.36-7.28 (m, 1H), 7.28-7.18 (m, 1H), 7.17-7.08 (m, 2H), 6.44 (s, 1H), 3.93 (s, 2H), 3.41 (s, 3H), 2.75-2.62 (m, 4H), 2.59 (t, J =5.8 Hz, 2H), 2.55-2.51 (m, 1H), 1.79 (p, J =7.3 Hz, 2H); MS (CIAD ⁺ ) m/z 438 [M+H] ⁺ .

Example 205: 3-hydroxybutyl 4,4,8-trifluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxylate (Compound 304)

Example 205A: 4-nitrophenyl 6-(benzyloxy)-4,4,8-trifluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00767] To a solution of the product from Example 127P (100 mg, 0.211 mmol) in tetrahydrofuran (1 mL) was added triethylamine (0.035 mL, 0.253 mmol) followed by 4-nitrophenyl carbonyl chloride (63.7 mg, 0.316 mmol) at 0 °C. The mixture was stirred for 2 h at 20 °C. Then, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol=5:1) to give the title compound (80 mg, 0.135 mmol, yield 57.7%). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm 3.90-4.08 (m, 2H), 4.09-4.28 (m, 1H), 4.30-4.51 (m, 1H), 4.70 (br s, 1H), 4.89 (br s, 1H), 5.26 (s, 2H), 7.25 (s, 1H), 7.27-7.40 (m, 3H), 7.43-7.61 (m, 4H), 8.29 (d, J= 9.01 Hz, 2H).

Example 205B: 3-hydroxybutyl 6-(benzyloxy)-4,4,8-trifluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00768] To a solution of the product from Example 205A (80 mg, 0.122 mmol) in tetrahydrofuran (1 mL) was added butane-1,3-diol (32.9 mg, 0.365 mmol) followed by potassium tert-butoxide (40.9 mg, 0.365 mmol) at 0 °C. The mixture was stirred for 1 h at 20 °C. The mixture was diluted with water (10 mL), extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (40 mg, 0.074 mmol, 54.5% yield), which was used in the next step without further purification. MS (ESI ^- ) m/z 542 [MH] ^- .

Example 205C: 3-hydroxybutyl 4,4,8-trifluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00769] A mixture of wet Pd(OH) ₂ /C (9.30 mg, 50%) and the product from Example 205B (40 mg, 0.066 mmol) in tetrahydrofuran (2 mL) was stirred under _H2 (15 psi) at 20°C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC on a ^Phenomenex® C18 Gemini-NX 3 μm 150×30 mm column eluting with a gradient _of acetonitrile (A) and 10 mM _NH4HCO3 in water (B) at a flow rate of 60 mL/min (0-8 min linear gradient 1-25% A, 8-10 min 100% A) to give the title compound (12 mg, _0.026 mmol, 38.3% yield) after lyophilization. ¹ H NMR (400 MHz, DMSO- d6 ) δ ppm 1.06 (d, J = 6.11 Hz, 3H), 1.48-1.77 (m, 2H), 3.64-3.79 (m, 1H), 4.01 (s, 2H), 4.03-4.10 (m, 2H), 4.10-4.19 (m, 2H), 4.55 (br s, 2H), 6.96 (s, 1H); MS (ESI ^- ) m/z 452 [MH] ^- .

Example 206: 5-(2-{[(2-cyclobutylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro- 1H -inden-5-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 305)

[00770] To a suspension of the product from Example 168L (150 mg, 0.349 mmol) in dichloromethane (1.75 mL) and ethanol (1.5 mL) was added triethylamine (0.068 mL, 0.489 mmol). The reaction mixture was stirred at ambient temperature for 5 min. 2-Cyclobutylacetaldehyde (44.6 mg, 0.454 mmol) in dichloromethane (0.5 mL) was then added and the reaction mixture was stirred for an additional 18 h at ambient temperature. Sodium tetrahydroborate (33.0 mg, 0.873 mmol) was then added and the resulting mixture was stirred for an additional 4 h. The reaction mixture was diluted with methanol and concentrated with diatomaceous earth to dry loading. The product was purified by reversed-phase column chromatography (120 g Agela Technologies Claricep™ Flash C18 100 column 40-60 μm, flow rate 50 ml/min, 10 to 100% CH ₃ OH in water [buffered with 0.025 M aqueous ammonium bicarbonate, adjusted to pH 7 with CO2 (s)]) to give the title compound (12.2 mg, 0.031 mmol, yield 8.79%). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm. 7.26 (s, 1H), 6.66 (s, 1H), 6.48 (m, 1H), 3.95-3.92 (m, 2H), 3.16-3.11 (m, 1H), 3.06-2.98 (m, 1H), 2.92-2.80 (m, 1H), 2.80-2.74 (m, 1H), 2.71-2.63 (m, 1H), 2.59-2.52 (m, 1H), 2.44-2.38 (m, 2H), 2.66-2.34 (m, 1H), 2.21-2.13 (m, 1H), 2.09-2.08 (m, 1H), 2.03-1.96 (m, 2H), 1.86-1.76 (m, 1H), 1.62-1.55 (m, 2H), 1.55-1.47 (m, 2H); MS (APCI ⁺ ) m/z 398 [M+H] ⁺ .

Example 207: 5-{2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 306)

Example 207A: Ethyl 2-(3,5-dimethylisoxazol-4-yl)acetate

[00771] To a solution of the product from Example 127A (6 g, 32.2 mmol) in ethanol (60 mL) was added K ₂ CO ₃ (8.91 g, 64.4 mmol) followed by hydroxylamine hydrochloride (3.36 g, 48.3 mmol) at 20 °C. The mixture was heated at 80 °C for 3 h. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (4.4 g, 24.0 mmol, 74.5% yield), which was used in the next step without purification. MS (ESI ⁺ ) m/z 184 [M+H] ⁺ .

Example 207B: 2-(3,5-dimethylisoxazol-4-yl)ethanol

[00772] To a solution of the product from Example 207A (4.5 g, 24.56 mmol) in tetrahydrofuran (2 mL) was added LiAlH ₄ (1.865 g, 49.1 mmol) in portions at 0 °C. The mixture was stirred at 20 °C for 2 h and then quenched at 20 °C with the sequential addition of water (0.1 mL), aqueous NaOH (0.1 mL, 15% in water), and water (0.3 mL). The mixture was then filtered and the filtrate was concentrated under reduced pressure to give the title compound (2 g, 14.2 mmol, 51.9% yield), which was used in the next step without further purification. MS (ESI ⁺ ) m/z 142 [M+H] ⁺ .

Example 207C: 2-(3,5-dimethylisoxazol-4-yl)acetaldehyde

[00773] To a solution of the product from Example 207B (700 mg, 4.46 mmol) in dichloromethane (2 mL) was added Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1 H )-one) (2839 mg, 6.69 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (460 mg, 3.30 mmol, yield 66.7%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.11-2.24 (m, 3H), 2.30-2.43 (m, 3H), 3.43 (d, J= 1.47 Hz, 2H), 9.67 (t, J= 1.71 Hz, 1H).

Example 207D: 5-{6-(benzyloxy)-2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-4,4,8-trifluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00774] The title compound was prepared using the procedures described for Example 127Q at 207°C in 43.1% yield. MS (ESI ^- ) m/z 549 [MH] ^- .

Example 207E: 5-{2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00775] The title compound was prepared using the procedures described for Example 127R from 207D in 48.3% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.17 (s, 3H), 2.30 (s, 3H), 2.56 (br d, J = 7.50 Hz, 3H), 2.67 (br s, 2H), 3.17 (br t, J = 11.44 Hz, 2H), 3.65 (br s, 2H), 4.03 (s, 2H), 6.91 (s, 1H), 6.95 (s, 1H), 6.95 (s, 1H), 7.08 (s, 1H), 7.20 (s, 1H), 10.07 (br s, 1H); MS (ESI ^- ) m/z 459 [MH] ^- .

Example 208: 5-[(7 R )-1-fluoro-3-hydroxy-7-{[(3 R )-3-hydroxybutyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 307)

Example 208A: 5-[3-(benzyloxy)-1-fluoro-7-{[(3R)-3-hydroxybutyl]amino}-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00776] To a solution of the product from Example 67F (0.537 g, 1.327 mmol) in ethanol (11 mL) were added (2 R )-4-aminobutan-2-ol hydrochloride (0.250 g, 1.99 mmol) and triethylamine (0.555 mL, 3.98 mmol). After 30 min, sodium cyanoborohydride (0.100 g, 1.592 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.151 mL, 7.96 mmol), then diluted with acetonitrile (10 mL) and water (2 mL). ^Celite® (5 g) was added and the mixture was concentrated in vacuo. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.4591 g, 0.961 mmol, 72.4% yield). MS ( ^APCI ) m/z 478 [M+H] ⁺ .

Example 208B: 5-(1-fluoro-3-hydroxy-7-{[(3R)-3-hydroxybutyl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl) ^-1λ6.2 , 5-thiadiazolidine-1,1,3-trione

[00777] To a suspension of the product from Example 208A (0.4591 g, 0.961 mmol) and pentamethylbenzene (0.275 g, 1.857 mmol) in dichloromethane (9 mL) at -78 °C was added a solution of boron trichloride (13.9 mL, 1 M in dichloromethane, 13.9 mmol) slowly down the side of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (4.6 mL) and then ethanol (4.6 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 9 mL), 1:1 ethyl acetate/heptanes (2 x 5 mL), dichloromethane (2 x 5 mL), and acetonitrile (2 x 4.6 mL) to give a gummy solid. The crude product was dissolved in methanol (15 mL) and ^Celite® (5 g) was added and the resulting mixture was concentrated under reduced pressure to give a powder which was dry loaded onto a Teledyne ISCO 100 g reverse phase C18 column and purified with a gradient of 10-100% methanol in buffer (0.025 M ammonium carbonate in water, adjusted to pH 7 with dry ice), monitoring at 206 nm to give the title compound (0.2464 g, 0.636 mmol, 66.2% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm. 9.23 (s, 1H), 8.44 (s, 2H), 6.47 (d, J =1.4 Hz, 1H), 4.83 (s, 1H), 3.94 (s, 2H), 3.74 (dddd, J =8.3, 6.4, 4.0, 2.3 Hz, 1H), 3.45 (s, 1H), 3.11 (ddd, J =21.0, 17.4, 5.3 Hz, 3H), 2.77 (tp, J =17.2, 5.2 Hz, 2H), 2.59-2.50 (m, 1H), 2.15 (d, J =12.2 Hz, 1H), 1.80-1.54 (m, 3H), 1.11 (d, J =6.1 Hz, 3H); MS (CIAD ⁺ ) m/z 388 [M+H] ⁺ .

Example 208C: 5-[(7R)-1-fluoro-3-hydroxy-7-{[(3R)-3-hydroxybutyl]amino}-5,6,7,8-tetrahydronaphthalene-2-yl]-1λ ^6,2,5 -thiadiazolidine-1,1,3-trione

[00778] The product from Example 208B (0.2464 g, 0.636 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a CO ₂ pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical CO ₂ supplied by a 350 psi dewar of bone dry non-certified CO ₂ with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 40% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm x 250 mm id CHIRALPAK® IC column with 5 μm particles. The late eluting enantiomer peak gave the title compound (0.0569 g, 0.147 mmol, 46.2% yield). ¹ H NMR and MS data were identical to those of Example 208B. The absolute stereochemistry was tentatively assigned by analogy with the chromatographic elution order for the product of Example 19.

Example 209: 5-{(7 R )-1-fluoro-3-hydroxy-7-[(4-hydroxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 308)

Example 209A: 5-{3-(benzyloxy)-1-fluoro-7-[(4-hydroxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00779] To a solution of the product from Example 67F (0.439 g, 1.085 mmol) in ethanol (8.8 mL) were added 4-amino-2,2-dimethylbutan-1-ol hydrochloride (0.250 g, 1.627 mmol) and triethylamine (0.454 mL, 3.25 mmol). After 30 min, sodium cyanoborohydride (0.082 g, 1.302 mmol) was added as a solid. After 16 h, the reaction mixture was quenched with ammonium hydroxide (0.123 mL, 6.51 mmol), then diluted with acetonitrile (10 mL) and water (2 mL). ^Celite® (4 g) was added and the mixture was concentrated in vacuo to give a powder. The resulting mixture was loaded dry onto a Teledyne ISCO 275 g reversed phase C18 column and eluted with a gradient of 10-100% methanol in buffer (0.025 M ammonium bicarbonate in water acidified to pH 7 with dry ice) to give the title compound (0.4332 g, 0.857 mmol, 79% yield). MS (APCI ⁾ m/z 506 [M+H] ⁺ .

Example 209B: 5-{1-fluoro-3-hydroxy-7-[(4-hydroxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione, hydrochloride salt

[00780] To a suspension of the product from Example 209A (0.4332 g, 0.857 mmol) and pentamethylbenzene (0.246 g, 1.658 mmol) in dichloromethane (8.6 mL) at -78 °C was added a solution of boron trichloride (12.4 mL, 1 M in dichloromethane, 12.4 mmol) slowly down the side of the flask. The resulting mixture was stirred for 5 min, then warmed to an internal temperature of 0 °C, then cooled to -78 °C and quenched with ethyl acetate (4.3 mL) followed by ethanol (4.3 mL). The reaction mixture was warmed to ambient temperature and concentrated in vacuo. The crude solid was triturated with heptanes (3 x 9 mL), 1:1 ethyl acetate/heptanes (2 x 5 mL), dichloromethane (2 x 5 mL), and acetonitrile (2 x 2.5 mL) to give the title compound as the hydrochloride salt (0.2511 g, 0.556 mmol, 67.0% yield). ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm. 10.05 (s, 1H), 8.84 (dt, J =23.9, 5.9 Hz, 1H), 6.53 (d, J =1.3 Hz, 1H), 4.28 (s, 2H), 3.44 (k, J =7.0 Hz, 2H), 3.16-3.08 (m, 3H), 3.01 (dk, J =11.9, 6.3 Hz, 2H), 2.82 (dt, J =17.3, 4.5 Hz, 1H), 2.74 (ddd, J =17.3, 11.5, 5.5 Hz, 1H), 2.59 (dd, J =16.1, 10.1 Hz, 1H), 2.24-2.18 (m, 1H), 1.72 (cd, J =11.8, 5.5 Hz, 1H), 1.62-1.55 (m, 2H), 0.85 (s, 6H); MS (CIAD ⁺ ) m/z 416 [M+H] ⁺ .

Example 209C: 5-{(7R)-1-fluoro-3-hydroxy-7-[(4-hydroxy-3,3-dimethylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ 6,2,5-thiadiazolidine-1,1,3-trione

[00781] The product from Example 209B (0.2511 g, 0.556 mmol) was separated by preparative chiral SFC. Preparative SFC was performed on a THAR/Waters SFC 80 system running SuperChrom™ software. The preparative SFC system was equipped with an 8-position preparative column selector, a _CO2 pump, a modifier pump, an automatic backpressure regulator (ABPR), a UV detector, and a 6-position fraction collector. The mobile phase consisted of supercritical _CO2 supplied by a 350 psi dewar of bone dry, non-certified _CO2 with methanol modifier (0.1% triethylamine) at a flow rate of 70 g/min. The column was maintained at ambient temperature and the backpressure regulator was set to maintain 100 bar. The sample was dissolved in methanol:dimethyl sulfoxide (70:30) at a concentration of 5 mg/mL. The sample was loaded into the modifier stream in 2 mL injections (10 mg). The mobile phase was maintained isocratically at 40% cosolvent:CO ₂ . Fraction collection was time triggered. The instrument was equipped with a 21 mm x 250 mm id CHIRALPAK® IC column with 5 μm particles. The late eluting enantiomer peak gave the title compound (0.0624 g, 0.150 mmol, 54.1% yield). ¹ H NMR and MS data were identical to those of Example 209B. The absolute stereochemistry was tentatively assigned by analogy with the chromatographic elution order for the product of Example 19.

Example 210: 5-[1-fluoro-3-hydroxy-6-(3-hydroxy-3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 309)

Example 210A: 3-(benzyloxy)-1,6-dibromonaphthalene-2-amine

[00782] To a solution of 3-(benzyloxy)naphthalen-2-amine (International Patent Publication WO 2008148744; 4.34 g, 13.9 mmol) in CHCl ₃ (100 mL) was added dropwise Br ₂ (1.58 mL, 30.6 mmol) in CHCl ₃ (20 mL) at room temperature and stirring was continued for 12 h. The mixture was poured into saturated NaHCO ₃ solution (100 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate (3×100 mL) and all organic layers were combined, dried over MgSO ₄ , filtered and concentrated to give the title compound (8.10 g, 11.9 mmol, yield 86%, purity 60%). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 5.30 (s, 2H), 5.51 (s, 2H), 7.40-7.47 (m, 5H), 7.57 (d, J =7.5 Hz, 2H), 7.72 (d, J =8.8 Hz, 1H), 7.92 (d, J =2.2 Hz, 1H).

Example 210B: 3-(benzyloxy)-6-bromonaphthalene-2-amine

[00783] To a solution of Example 210A (16.0 g, 39.3 mmol) in ethanol (640 mL) at room temperature was added tin (5.60 g, 47.2 mmol) in one portion, followed by concentrated HCl (160 mL), and the mixture was heated at 90 °C for one hour. The reaction mixture was cooled to room temperature and poured into saturated NaHCO ₃ solution (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound (10 g, 21.3 mmol, 54% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 5.24 (s, 2H), 5.30 (s, 2H), 6.92 (s, 1H), 7.22-7.29 (m, 2H), 7.31-7.37 (m, 1H), 7.37-7.47 (m, 3H), 7.55 (d, J =7.0 Hz, 2H), 7.79 (d, J =2.0 Hz, 1H).

Example 210C: 3-(benzyloxy)-6-bromo-1-fluoronaphthalene-2-amine

[00784] To a solution of Example 210B (15 g, 32.0 mmol) in tetrahydrofuran (200 mL) was added N -fluoro- N- (phenylsulfonyl)benzenesulfonamide (10.6 g, 33.6 mmol) at room temperature and stirring was continued for 12 h. The mixture was quenched with aqueous sodium thiosulfate (20 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic fractions were washed with brine (20 mL), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with petroleum ether:ethyl acetate = 100:1 to 50:1 to give the title compound (7.3 g, 19 mmol, 59% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 5.21-5.33 (m, 4H), 7.25 (s, 1H), 7.3 2-7.38 (m, 1H), 7.40-7.46 (m, 3H), 7.55-7.60 (m, 2H), 7.63-7.68 (m, 1H), 7.93 (t, J = 1.7 Hz, 1H).

Example 210D: methyl {[3-(benzyloxy)-6-bromo-1-fluoronaphthalene-2-yl]amino}acetate

[00785] To a solution of Example 210C (7.3 g, 19.0 mmol) in N,N -dimethylformamide (30 mL) were added N,N -diisopropylethylamine (13 mL, 76 mmol) and methyl 2-bromoacetate (17.4 g, 114 mmol) at ambient temperature, and the mixture was heated to 65 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×80 mL). The combined organic fractions were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether:ethyl acetate = 5:1 (30 mL), then filtered to give the title compound (5.6 g, 10.7 mmol, 56% yield). ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 3.62 (s, 3H), 4.21 (dd, J =6.7, 3.9 Hz, 2H), 5.28 (s, 2H), 5.59 (td, J =6.7, 2.4 Hz, 1H), 7.27 (s, 1H), 7.33-7.38 (m, 1H), 7.39-7.45 (m, 3H), 7.55 (d, J =7.1 Hz, 2H), 7.62 (d, J =8.8 Hz, 1H), 7.93 (s, 1H).

Example 210E: methyl {[3-(benzyloxy)-6-bromo-1-fluoronaphthalene-2-yl][(tert-butoxycarbonyl)sulfamoyl]amino}acetate

[00786] To a solution of sulfurisocyanatide chloride (2.87 g, _20.3 mmol) in _CH2Cl2 (4 mL) was added dropwise a solution of 2-methylpropan-2-ol (1.9 mL, ₂₀ mmol) in _CH2Cl2 (2.00 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. To this mixture was added a solution of Example 210D (5.3 g, 10 mmol) and triethylamine (5.65 mL, 40.5 mmol) in _CH2Cl2 (7 mL) at 0 °C. _The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was concentrated under reduced pressure to give the title compound (6 g, 9.7 mmol, 96% yield). The title compound was used in the next step without purification. ¹ H NMR (400 MHz, DMSO _-d6 ) δ ppm 1.30 (s, 9H), 3.53 (s, 3H), 4.45 (d, J =18.0 Hz, 1H), 4.76 (d, J =18.0 Hz, 1H), 5.17-5.35 (m, 2H), 7.31-7.37 (m, 2H), 7.38-7.44 (m, 2H), 7.52-7.62 (m, 3H), 7.92 (d, J =8.8 Hz, 1H), 8.12 (s, 1H).

Example 210F: methyl {[3-(benzyloxy)-6-bromo-1-fluoronaphthalene-2-yl](sulfamoyl)amino}acetate

[00787] To a solution of Example 210E (7 g, 11 mmol) in CH ₂ Cl ₂ (100 mL) was added trifluoroacetic acid (20 mL, 260 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The pH was adjusted to approximately 8 by gradually adding aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (4.6 g, 8.4 mmol, 74% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.51-3.60 (m, 3H), 4.25-4.37 (m, 1H), 4.42-4.54 (m, 1H), 5.18-5.36 (m, 2H), 7.10 (s, 2H), 7.31-7.47 (m, 4H), 7.55-7.62 (m, 3H), 7.92 (d, J =8.9 Hz, 1H), 8.15 (s, 1H).

Example 210G: 5-[3-(benzyloxy)-6-bromo-1-fluoronaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00788] To a solution of Example 210F (4.6 g, 8.42 mmol) in tetrahydrofuran (50 mL) at room temperature was added 4 g of activated molecular sieves 4 and sodium methanolate in methanol (3.62 g, 12.63 mmol). The mixture was stirred at room temperature for 15 min. The reaction was quenched by adding 60 mL of 1 N HCl and extracted with ethyl acetate (3 _× 100 mL). The combined organic fractions were washed with brine (100 mL), dried over _Na2SO4 , _filtered and concentrated under reduced pressure to give the title compound (3.7 g, 6.9 mmol, 82% yield). ¹ H NMR (400 MHz, DMSO -d6 ) δ ppm. 4.38 (s, 2H), 5.26 (s, 2H), 7.31-7.41 (m, 3H), 7.44 (s, 1H), 7.53 (d, J =7.0 Hz, 2H), 7.60 (dd, J =8.9, 1.8 Hz, 1H), 7.92 (d, J =8.9 Hz, 1H), 8.16 (s, 1H).

Example 210H: 5-[3-(benzyloxy)-1-fluoro-6-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00789] To the vial were added 5-[3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 210G, 0.150 g, 0.322 mmol), methanesulfonato(2-(di- tert -butylphosphino)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.005 g, 0.006 mmol), and cesium carbonate (0.315 g, 0.967 mmol). The vial was sealed, evacuated, and backfilled with nitrogen. The pump/fill cycle was repeated three more times. Degassed N,N'- dimethylformamide (1.1 mL) was added, followed by a solution of 3-methylbutane-1,3-diol (0.168 g, 1.61 mmol) in degassed N,N'- dimethylformamide (0.54 mL). The vial was heated to 80 °C. After 2 h, the vial was cooled to ambient temperature, after which 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (0.050 g, 0.19 mmol) was added to convert 5-[3-(benzyloxy)-1-fluoro-6-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, a by-product, to the desired product. The mixture was stirred at ambient temperature for 60 h and then the reaction mixture was partitioned between 1 M hydrochloric acid (40 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.086 g, 0.18 mmol, 54% yield). ¹ H NMR (500 MHz, DMSO _-d6 ) δ ppm 7.88 (d, J =9.1 Hz, 1H), 7.54-7.49 (m, 2H), 7.42-7.36 (m, 2H), 7.36-7.31 (m, 3H), 7.11 (dd, J =9.1, 2.4 Hz, 1H), 5.25 (s, 2H), 4.50 (s, 2H), 4.21 (t, J =7.2 Hz, 2H), 1.91 (t, J =7.1 Hz, 2H), 1.19 (s, 6H); MS (CIAD ⁺ ) m/z 488.2 [M+H] ⁺ .

Example 210I: 5-[1-fluoro-3-hydroxy-6-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00790] The product from Example 210H (0.079 g, 0.16 mmol), ammonium formate (0.061 g, 0.97 mmol), and ethanol (0.80 mL) were charged to a vial. The vial was purged with nitrogen, then 10% palladium on carbon (0.017 g, 0.016 mmol) was added. The vial was capped, purged with nitrogen, and heated to 60 °C. After 2 h, the vial was cooled to ambient temperature and the reaction mixture was filtered through diatomaceous earth with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.032 g, 0.081 mmol, 50% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 10.53 (lat s, 1H), 7.80 (d, J =9.1 Hz, 1H), 7.21 (s, 1H), 7.03-6.99 (m, 2H), 4.46 (s, 2H), 4.18 (t, J =7.2 Hz, 2H), 1.89 (t, J =7.2 Hz, 2H), 1.19 (s, 6H); MS (ESI ⁺ ) m/z 381.0 [MH ₂ O+H] ⁺ .

Example 210J: 5-[1-fluoro-3-hydroxy-6-(3-hydroxy-3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00791] In a Parr shaker, 10% palladium on carbon (0.039 g, 0.0555 mmol, 50 wt % in water) was added to a solution of the product from Example 210I (0.0393 g, 0.099 mmol) in trifluoroethanol (4 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (5 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice) at 206 nM to give the title compound (2.2 mg, 5.2 μmol, 5.3% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 8.94 (lat s, 1H), 7.07 (lat s, 4H), 6.41 (s, 1H), 4.15 (s, 1H), 3.92 (s, 2H), 3.70-3.64 (m, 1H), 3.62-3.50 (m, 2H), 2.89 (dd, J = 16.8, 4.5 Hz, 1H), 2.68-2.51 (m, 3H), 1.93-1.87 (m, 1H), 1.72 (dt, J = 13.1, 6.6 Hz, 1H), 1.67 (s, 1H), 1.08 (s, 6H); MS (IER ^- ) m/z 401 [MH] ^- .

Example 211: 5-[6-(cyclopropylmethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3 -trione (Compound 310)

Example 211A: 5-[3-(benzyloxy)-1-fluoro-6-hydroxynaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00792] To the vial were added 5-[3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 210G, 0.250 g, 0.537 mmol), methanesulfonato(2-(di- tert -butylphosphino)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.005 g, 0.005 mmol), 2-(di- tert -butylphosphino)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl (0.003 g, 0.005 mmol) and cesium carbonate (0.525 g, 1.61 mmol). The vial was sealed, evacuated and backfilled with nitrogen. The evacuation/fill cycle was repeated three more times. A degassed mixture of water (0.058 mL, 3.2 mmol) and N,N -dimethylacetamide (2.7 mL) was then added. The vial was heated to 80 °C. After 4 h, the vial was cooled to ambient temperature and the reaction mixture was partitioned between 1 M hydrochloric acid (50 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (4 × 30 mL). The ammonium chloride washes were combined and back-extracted with ethyl acetate (30 mL). The organic phases were combined, washed with brine/1 M hydrochloric acid (4:1 v/v) (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [column 120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.159 g, 0.395 mmol, 74% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.15 (br. s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.55-7.46 (m, 2H), 7.41-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.22 (s, 1H), 7.10 (t, J = 2.0 Hz, 1H), 7.04 (dd, J =9.0, 2.3 Hz, 1H), 5.23 (s, 2H), 4.48 (s, 2H); MS (CIAD ⁺ ) m/z 403.3 [M+H] ⁺ .

Example 211B: 5-[3-(benzyloxy)-6-(cyclopropylmethoxy)-1-fluoronaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00793] To the vial were added the product from Example 211A (0.100 g, 0.249 mmol), (bromomethyl)cyclopropane (0.067 g, 0.50 mmol), cesium carbonate (0.243 g, 0.746 mmol), and N,N -dimethylformamide (0.99 mL). The resulting mixture was stirred at ambient temperature. After 14 h, the reaction mixture was partitioned between 1 M hydrochloric acid (25 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (3 x 15 mL). The ammonium chloride washes were combined and back-extracted with ethyl acetate (15 mL). The organic layers were combined, washed with brine/1 M hydrochloric acid (4:1 v/v) (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.084 g, 0.18 mmol, 74% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 7.88 (d, J =9.1 Hz, 1H), 7.52-7.50 (m, 2H), 7.40-7.36 (m, 2H), 7.35-7.32 (m, 1H), 7.31 (s, 1H), 7.27 (t, J =1.8 Hz, 1H), 7.14 (dd, J =9.1, 2.4 Hz, 1H), 5.25 (s, 2H), 4.51 (s, 2H), 3.95 (d, J =7.0 Hz, 2H), 1.34-1.24 (m, 1H), 0.65-0.55 (m, 2H), 0.41-0.31 (m, 2H); MS (CIAD ⁺ ) m/z 456.2 [M+H] ⁺ .

Example 211C: 5-[6-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00794] A vial was charged with the product from Example 211B (0.074 g, 0.16 mmol), ammonium formate (0.061 g, 0.97 mmol), and ethanol (0.81 mL). The vial was purged with nitrogen, then 10% palladium on carbon (0.017 g, 0.016 mmol) was added. The vial was capped, purged with nitrogen, and heated to 50 °C. After 1.5 h, the vial was cooled to ambient temperature, and the reaction mixture was filtered through diatomaceous earth with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.050 g, 0.14 mmol, 84% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.57 (br s, 1H), 7.80 (d, J =9.1 Hz, 1H), 7.16 (t, J =1.9 Hz, 1H), 7.04 (dd, J =9.1, 2.4 Hz, 1H), 6.99 (s, 1H), 4.49 (s, 2H), 3.93 (d, J =7.0 Hz, 2H), 1.34-1.22 (m, 1H), 0.62-0.57 (m, 2H), 0.39-0.33 (m, 2H); MS (CIAD ⁺ ) m/z 367.3 [M+H] ⁺ .

Example 211D: 5-[6-(cyclopropylmethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00795] In a Parr shaker, 10% palladium on carbon (0.044 g, 0.0627 mmol, 50 wt % in water) was added to a solution of the product from Example 211C (0.0443 g, 0.121 mmol) in trifluoroethanol (4.8 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (4 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. ^Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to ₇ with dry ice) at 206 nM to give the title compound (4.5 mg, 0.012 mmol, 7.3% yield). ¹ H NMR (600 MHz, DMSO- d6 ) δ ppm 8.96 (lat s, 1H), 7.08 (lat s, 4H), 6.41 (s, 1H), 3.92 (s, 2H), 3.70 (dddd, J =9.2, 7.1, 4.4, 2.5 Hz, 1H), 3.30 (d, J =6.7 Hz, 2H), 2.89 (dd, J =16.6, 4.6 Hz, 1H), 2.67-2.56 (m, 2H), 2.53-2.48 (m, 1H), 1.92-1.85 (m, 1H), 1.71 (dtd, J =13.5, 7.9, 5.8 Hz, 1H), 0.98 (ttt, J =8.0, 6.8, 4.9 Hz, 1H), 0.48-0.40 (m, 2H), 0.18-0.12 (m, 2H); MS (ESI ^- ) m/z 369 [MH] ^- .

Example 212: 5-{6-[(4,4-difluorobutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 311)

Example 212A: 5-{3-(benzyloxy)-6-[(4,4-difluorobutyl)amino]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt

[00796] To the vial were added 5-[3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 210G, 0.150 g, 0.322 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.015 g, 0.016 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (0.009 g, 0.016 mmol), 4,4-Difluorobutan-1-amine hydrochloride (0.094 g, 0.65 mmol) and cesium carbonate (0.420 g, 1.29 mmol). The vial was sealed, evacuated and backfilled with nitrogen. The evacuation/fill cycle was repeated three more times. Degassed N,N -dimethylformamide (1.6 mL) was added and the vial was heated to 80 °C. After 22 h, the vial was cooled to ambient temperature and the reaction mixture was partitioned between 1 M hydrochloric acid (40 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.088 g, 0.18 mmol, 55% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.67 (d, J =9.0 Hz, 1H), 7.52-7.48 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.06 (s, 1H), 6.92 (dd, J =8.9, 2.0 Hz, 1H), 6.67 (t, J =2.0 Hz, 1H), 6.14 (tt, J =56.8, 4.4 Hz, 1H), 5.21 (s, 2H), 4.46 (s, 2H), 3.17 (t, J =7.0 Hz, 2H), 2.03-1.86 (m, 2H), 1.72 (dk, J =10.6, 7.2 Hz, 2H); MS (CIAD ⁺ ) m/z 494.2 [M+H] ⁺ .

Example 212B: 5-{6-[(4,4-difluorobutyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt

[00797] A vial containing a suspension of the product from Example 212A (0.085 g, 0.17 mmol) and 1,2,3,4,5-pentamethylbenzene (0.076 g, 0.51 mmol) in dichloromethane (1.7 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.4 mL, 1.4 mmol) was then added. The resulting mixture was stirred at -78 °C for 10 min, then the dry ice-acetone bath was replaced with an ice/water bath. After 1 hour, the vial was recooled to -78 °C. The reaction mixture was diluted with dichloromethane (3 mL) and quenched by the sequential addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was allowed to warm to ambient temperature and stirred for 15 min before concentration under reduced pressure. The residue was co-evaporated with ethanol (2 x 5 mL) and purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.050 g, 0.12 mmol, 72% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.23 (br s, 1H), 7.61 (d, J =9.0 Hz, 1H), 6.84 (dd, J =9.1, 2.1 Hz, 1H), 6.76 (s, 1H), 6.54 (s, 1H), 6.13 (tt, J =56.9, 4.4 Hz, 1H), 4.44 (s, 2H), 3.16 (t, J =7.0 Hz, 2H), 2.02-1.86 (m, 2H), 1.77-1.64 (m, 2H); MS (CIAD ⁺ ) m/z 404.3 [M+H] ⁺ .

Example 212C: 5-{6-[(4,4-difluorobutyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00798] In a Parr shaker, 10% palladium on carbon (0.0416 g, 0.0592 mmol, 50 wt % in water) was added to a solution of the product from Example 212B (0.0416 g, 0.103 mmol) in trifluoroethanol (4 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (5 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice) at 206 nM to give the title compound (7.5 mg, 0.018 mol, 18% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 9.18 (br s, 1H), 8.42 (br s, 2H), 6.48 (s, 1H), 6.15 (tt, J =56.6, 4.2 Hz, 1H), 3.93 (s, 2H), 3.42 (s, 1H), 3.13-3.04 (m, 3H), 2.79 (dt, J =16.9, 4.9 Hz, 1H), 2.71 (dd, J =16.4, 9.8 Hz, 1H), 2.57 (dd, J =16.7, 10.7, 6.0 Hz, 1H), 2.21-2.15 (m, 1H), 2.00-1.87 (m, 1H), 1.78-1.64 (m, 3H); MS (ESI ⁺ ) m/z 408 [M+H] ⁺ .

Example 213: 5-[6-(4,4-difluorobutoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 312)

Example 213A: 5-[3-(benzyloxy)-6-(4,4-difluorobutoxy)-1-fluoronaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00799] To the vial were added the product from Example 211A (0.100 g, 0.249 mmol), 4-bromo-1,1-difluorobutane (0.086 g, 0.50 mmol), cesium carbonate (0.243 g, 0.746 mmol), and N,N -dimethylformamide (0.99 mL). The resulting mixture was stirred at ambient temperature. After 14 h, the reaction mixture was partitioned between 1 M hydrochloric acid (25 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (3 x 15 mL). The ammonium chloride washes were combined and back-extracted with ethyl acetate (15 mL). The organic layers were combined, washed with brine/1 M hydrochloric acid (4:1 v/v) (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.077 g, 0.16 mmol, 63% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.89 (d, J =9.1 Hz, 1H), 7.55-7.48 (m, 2H), 7.42-7.36 (m, 2H), 7.36-7.31 (m, 2H), 7.31 (t, J =1.9 Hz, 1H), 7.15 (dd, J =9.1, 2.4 Hz, 1H), 6.19 (tm, J =56.7, 4.3 Hz, 1H), 5.26 (s, 2H), 4.51 (s, 2H), 4.15 (t, J =6.3 Hz, 2H), 2.09-1.95 (m, 2H), 1.95-1.85 (m, 2H); MS (CIAD ⁺ ) m/z 495.3 [M+H] ⁺ .

Example 213B: 5-[6-(4,4-difluorobutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00800] A vial was charged with the product from Example 213A (0.056 g, 0.11 mmol), ammonium formate (0.043 g, 0.68 mmol), and ethanol (0.57 mL). The vial was purged with nitrogen, then 10% palladium on carbon (0.012 g, 0.011 mmol) was added. The vial was capped, purged with nitrogen, and heated to 50 °C. After 1.5 h, the vial was cooled to ambient temperature, and the reaction mixture was filtered through diatomaceous earth with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.039 g, 0.095 mmol, 84% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.57 (broad s, 1H), 7.82 (d, J =9.1 Hz, 1H), 7.20 (t, J =1.9 Hz, 1H), 7.04 (dd, J =9.1, 2.4 Hz, 1H), 7.01 (s, 1H), 6.18 (tm, J =56.8, 4.4 Hz, 1H), 4.48 (s, 2H), 4.14 (t, J =6.3 Hz, 2H), 2.09-1.95 (m, 2H), 1.94-1.84 (m, 2H); MS (CIAD ⁺ ) m/z 405.3 [M+H] ⁺ .

Example 213C: 5-[6-(4,4-difluorobutoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00801] In a Parr shaker, 10% palladium on carbon (0.074 g, 0.105 mmol, 50 wt % in water) as a solid was added to a solution of the product from Example 213B (0.0742 g, 0.150 mmol) in trifluoroethanol (6 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (5 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice) at 206 nM to give the title compound (15.0 mg, 0.350 mol, 23.5% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 8.96 (br s, 1H), 7.07 (br s, 3H), 6.41 (s, 1H), 6.07 (tt, J =57.0, 4.5 Hz, 1H), 3.92 (s, 2H), 3.68 (s, 1H), 3.55-3.43 (m, 2H), 2.90 (dd, J =16.6, 4.5 Hz, 1H), 2.68-2.60 (m, 2H), 2.60-2.51 (m, 1H), 1.98-1.77 (m, 3H), 1.75-1.68 (m, 1H), 1.60 (p, J =6.6 Hz, 2H); MS (IER ^- ) m/z 424 [MH] ^- .

Example 214: 5-{1-fluoro-3-hydroxy-6-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 313)

Example 214A: 5-{3-(benzyloxy)-1-fluoro-6-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00802] 5-[3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 210G, 0.150 g, 0.322 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.015 g, 0.016 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (0.009 g, 0.02 mmol) were added to the vial. and cesium carbonate (0.315 g, 0.967 mmol). A solution of 3-methylbutan-1-amine (0.056 g, 0.65 mmol) in degassed N,N -dimethylformamide (1.6 mL) was added and the flask was heated to 80 °C. After 2 h, the flask was cooled to ambient temperature and the reaction mixture was partitioned between 1 M hydrochloric acid (40 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to afford the title compound as the corresponding trifluoroacetic acid salt (0.137 g, 0.234 mmol, 73% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.67 (d, J =9.0 Hz, 1H), 7.50 (d, J =7.0 Hz, 2H), 7.42-7.35 (m, 2H), 7.35-7.29 (m, 1H), 7.08 (s, 1H), 6.94 (dd, J =9.1, 2.1 Hz, 1H), 6.67 (s, 1H), 5.21 (s, 2H), 4.48 (s, 2H), 3.11 (t, J =7.4 Hz, 2H), 1.72 (dk, J =13.3, 6.7 Hz, 1H), 1.51 (k, J =7.0 Hz, 2H), 0.94 (d, J =6.7 Hz, 6H); MS (ESI ⁺ ) m/z 472.0 [M+H] ⁺ .

Example 214B: 5-{1-fluoro-3-hydroxy-6-[(3-methylbutyl)amino]naphthalen-2-yl} ^-1λ6,2,5 -thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt

[00803] A vial containing a suspension of the product from Example 214A (0.129 g, 0.220 mmol) and 1,2,3,4,5-pentamethylbenzene (0.098 g, 0.66 mmol) in dichloromethane (2.2 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.8 mL, 1.8 mmol) was then added. The resulting mixture was stirred at -78 °C for 10 min, then the dry ice-acetone bath was replaced with an ice/water bath. After 1 hour, the vial was recooled to -78 °C. The reaction mixture was diluted with dichloromethane (3 mL) and quenched by the successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was allowed to warm to ambient temperature and stirred for 15 min before concentration under reduced pressure. The residue was co-evaporated with ethanol (2 x 5 mL) and purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.080 g, 0.21 mmol, 95% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.19 (lat s, 1H), 7.60 (d, J =9.0 Hz, 1H), 6.85 (dd, J =9.1, 2.1 Hz, 1H), 6.76 (s, 1H), 6.54 (t, J =1.9 Hz, 1H), 4.43 (s, 2H), 3.09 (t, J =7.3 Hz, 2H), 1.73 (dp, J =13.3, 6.6 Hz, 1H), 1.50 (k, J =7.0 Hz, 2H), 0.93 (d, J =6.6 Hz, 6H); MS (CIAD ⁺ ) m/z 382.3 [M+H] ⁺ .

Example 214C: 5-{1-fluoro-3-hydroxy-6-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00804] In a Parr shaker, 10% palladium on carbon (0.0674 g, 0.0960 mmol, 50 wt % in water) was added to a solution of the product from Example 214B (0.0674 g, 0.177 mmol) in trifluoroethanol (7 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (5 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice) at 206 nM to give the title compound (15.3 mg, 0.0400 mol, 22.5% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 9.18 (lat s, 1H), 8.41 (lat s, 2H), 6.49 (d, J =1.3 Hz, 1H), 3.93 (s, 2H), 3.47-3.42 (m, 1H), 3.11 (dd, J =16.3, 4.5 Hz, 1H), 3.02 (t, J =8.2 Hz, 2H), 2.80 (dt, J =16.7, 4.3 Hz, 1H), 2.73 (dd, J =16.3, 9.9 Hz, 1H), 2.57 (ddd, J =16.8, 10.9, 5.9 Hz, 1H), 2.23-2.17 (m, 1H), 1.75-1.60 (m, 2H), 1.50 (ddt, J = 10.1, 8.1, 4.0 Hz, 2H), 0.92 (d, J = 6.6 Hz, 6H); MS (IER ⁺ ) m/z 386 [M+H] ⁺ .

Example 215: 5-[1-fluoro-3-hydroxy-6-(3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 314)

Example 215A: 5-[3-(benzyloxy)-1-fluoro-6-(3-methylbutoxy)naphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00805] To the vial were added the product of Example 211A (0.100 g, 0.249 mmol), 1-bromo-3-methylbutane (0.075 g, 0.50 mmol), cesium carbonate (0.243 g, 0.746 mmol), and N,N -dimethylformamide (0.99 mL). The resulting mixture was stirred at ambient temperature. After 14 h, the reaction mixture was partitioned between 1 M hydrochloric acid (25 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (3 x 15 mL). The ammonium chloride washes were combined and re-extracted with ethyl acetate (15 mL). The organic layers were combined, washed with brine/1 M hydrochloric acid (4:1 v/v) (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.092 g, 0.20 mmol, 79% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.88 (d, J = 9.1 Hz, 1H), 7.53-7.49 (m, 2H), 7.41-7.37 (m, 2H), 7.36-7.30 (m, 3H), 7.12 (dd, J = 9.1, 2.4 Hz, 1H), 5.25 (s, 2H), 4.51 (s, 2H), 4.12 (t, J = 6.7 Hz, 2H), 1.82 (dp, J = 13.4, 6.7 Hz, 1H), 1.68 (q, J = 6.7 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H); MS (APCI ⁺ ) m/z 473.3 [M+H] ⁺ .

Example 215B: 5-[1-fluoro-3-hydroxy-6-(3-methylbutoxy)naphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00806] A vial was charged with the product from Example 215A (0.090 g, 0.19 mmol), ammonium formate (0.072 g, 1.1 mmol), and ethanol (0.96 mL). The vial was purged with nitrogen, then 10% palladium on carbon (0.020 g, 0.019 mmol) was added. The vial was capped, purged with nitrogen, and heated to 50 °C. After 1.5 h, the vial was cooled to ambient temperature, and the reaction mixture was filtered through diatomaceous earth with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.054 g, 0.14 mmol, 73% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.52 (lat s, 1H), 7.80 (d, J =9.1 Hz, 1H), 7.21 (t, J =1.9 Hz, 1H), 7.02 (dd, J =9.2, 2.3 Hz, 1H), 7.00 (s, 1H), 4.46 (s, 2H), 4.10 (t, J =6.7 Hz, 2H), 1.81 (dp, J =13.3, 6.7 Hz, 1H), 1.67 (k, J =6.7 Hz, 2H), 0.95 (d, J =6.7 Hz, 6H); MS (CIAD ⁺ ) m/z 383.2 [M+H] ⁺ .

Example 215C: 5-[1-fluoro-3-hydroxy-6-(3-methylbutoxy)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00807] In a Parr shaker, 10% palladium on carbon (0.0912 g, 0.130 mmol, 50 wt % in water) was added to a solution of the product from Example 215B (0.0912 g, 0.238 mmol) in trifluoroethanol (9.5 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (4 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice) at 206 nM to give the title compound (16.7 mg, 0.0410 mmol, 17.4% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 9.55 (br. s, 1H), 6.44 (d, J = 1.3 Hz, 1H), 4.17 (s, 2H), 3.71-3.63 (m, 1H), 3.50 (dt, J = 9.4, 6.7 Hz, 1H), 3.45 (dt, J = 9.4, 6.7 Hz, 1H), 2.90 (dd, J =16.9, 4.5 Hz, 1H), 2.68-2.49 (m, 3H), 1.89 (dtd, J =13.5, 7.6, 6.9, 3.8 Hz, 1H), 1.77-1.66 (m, 1H), 1.63 (dk, J =13.4, 6.7 Hz, 1H), 1.38 (k, J =7.0 Hz, 2H), 0.86 (dd, J =6.6, 2.1 Hz, 6H); MS (IER ^- ) m/z 385 [MH] ^- .

Example 216: 5-{1-fluoro-3-hydroxy-6-[(3-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 315)

Example 216A: 5-{3-(benzyloxy)-1-fluoro-6-[(3-hydroxy-3-methylbutyl)amino]naphthalen-2-yl} ^-1λ6,2,5 -thiadiazolidine-1,1,3-trione, trifluoroacetic acid salt

[00808] 5-[3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 210G, 0.150 g, 0.322 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.015 g, 0.016 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (0.009 g, 0.02 mmol) were added to the vial. and cesium carbonate (0.315 g, 0.967 mmol). The vial was sealed, evacuated, and backfilled with nitrogen. The evacuation/refill cycle was repeated three more times. A solution of 4-amino-2-methylbutan-2-ol (0.067 g, 0.65 mmol) in degassed N,N -dimethylformamide (1.6 mL) was added and the vial was heated to 80 °C. After 2 h, the vial was cooled to ambient temperature and the reaction mixture was partitioned between 1 M hydrochloric acid (40 mL) and ethyl acetate (30 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to give the title compound (0.098 g, 0.20 mmol, 62% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.67 (d, J =9.0 Hz, 1H), 7.50 (d, J =7.0 Hz, 2H), 7.41-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.09 (s, 1H), 6.92 (dd, J =9.0, 2.1 Hz, 1H), 6.67 (s, 1H), 5.21 (s, 2H), 4.47 (s, 2H), 3.17 (dd, J =9.8, 6.0 Hz, 2H), 1.73 (dd, J = 9.8, 6.0 Hz, 2H), 1.18 (s, 6H); MS (ESI ⁺ ) m/z 487.6 [M+H] ⁺ .

Example 216B: 5-{1-fluoro-3-hydroxy-6-[(3-hydroxy-3-methylbutyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00809] The product from Example 216A (0.092 g, 0.19 mmol), ammonium formate (0.072 g, 1.1 mmol), and ethanol (0.95 mL) were charged to a vial. The vial was purged with nitrogen, then 10% palladium on carbon (0.020 g, 0.019 mmol) was added. The vial was capped, purged with nitrogen, and heated to 50 °C. After 2 h, the vial was cooled to ambient temperature and the reaction mixture was filtered through diatomaceous earth with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.1% trifluoroacetic acid)] to afford the title compound as the corresponding trifluoroacetic acid salt (0.072 g, 0.14 mmol, 74% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 10.27 (br s, 1H), 7.61 (d, J =9.0 Hz, 1H), 6.85 (dd, J =9.1, 2.2 Hz, 1H), 6.78 (s, 1H), 6.57 (s, 1H), 4.46 (s, 2H), 3.22-3.08 (m, 2H), 1.76-1.67 (m, 2H), 1.17 (s, 6H); MS (CIAD ⁺ ) m/z 398.3 [M+H] ⁺ . Example 216C: 5-{1-fluoro-3-hydroxy-6-[(3-hydroxy-3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00810] In a Parr shaker, 10% palladium on carbon (0.0624 g, 0.0889 mmol, 50 wt % in water) was added to a solution of the product from Example 216B (0.0624 g, 0.122 mmol) in trifluoroethanol (4.9 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (5 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. ^Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to ₇ with dry ice) at 206 nM to give the title compound (19.2 mg, 0.0480 mol, 39.2% yield). ¹ H NMR (500 MHz, DMSO- d6 ) δ ppm. 9.17 (br s, 1H), 8.31 (br s, 2H), 6.49 (d, J = 1.3 Hz, 1H), 4.58 (br s, 1H), 3.93 (s, 2H), 3.47-3.42 (m, 1H), 3.19-3.04 (m, 3H), 2.84-2.68 (m, 2H), 2.57 (ddd, J = 16.8, 10.8, 5.9 Hz, 1H), 2.22-2.16 (m, 1H), 1.76-1.64 (m, 3H), 1.16 (s, 6H); MS (ESI ⁺ ) m/z 402 [M+H] ⁺ .

Example 217: tert -butyl (2-{[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]oxy}ethyl)carbamate (Compound 316)

Example 217A: tert-Butyl (2-{[7-(benzyloxy)-5-fluoro-6-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)carbamate

[00811] To the vial were added the product of Example 211A (0.100 g, 0.249 mmol), tert-butyl (2-chloroethyl)carbamate (0.223 g, 1.24 mmol), tetrabutylammonium bromide (0.040 g, 0.12 mmol), tribasic potassium phosphate (0.264 g, 1.24 mmol), and N,N -dimethylacetamide (0.99 mL). The vial was heated to 50 °C. After 5 h, the vial was cooled to ambient temperature and the reaction mixture was partitioned between 0.5 M hydrochloric acid (40 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (3 x 15 mL). The ammonium chloride washes were combined and re-extracted with ethyl acetate (15 mL). The organic layers were combined, washed with brine/1 M hydrochloric acid (4:1 v/v) (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound as the corresponding ammonium salt (0.111 g, 0.197 mmol, 79% yield). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.83 (d, J = 9.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.34 (t, J = 7.3 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.21-7.13 (m, 2H), 7.05 (dd, J = 9.1, 2.3 Hz, 1H), 5.18 (s, 2H), 4.12 (s, 2H), 4.06-4.01 (m, 2H), 3.33 (t, J = 5.4 Hz, 2H), 1.32 (s, 9H); MS (APCI ⁺ ) m/z 446.3 [MC(O)OC(CH ₃ ) ₃ +H] ⁺ .

Example 217B: tert-butyl (2-{[5-fluoro-7-hydroxy-6-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)naphthalene-2-yl] oxy}ethyl)carbamate

[00812] A vial was charged with the product from Example 217A (0.108 g, 0.192 mmol), ammonium formate (0.073 g, 1.2 mmol), and ethanol (0.96 mL). The vial was purged with nitrogen, then 10% palladium on carbon (0.020 g, 0.019 mmol) was added. The vial was capped, purged with nitrogen, and heated to 50 °C. After 1 h, the vial was cooled to ambient temperature and the reaction mixture was filtered through diatomaceous earth with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g spherical column C18 100 40-60 µm Agela Claricep™, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound as the corresponding ammonium salt (0.081 g, 0.17 mmol, 90% yield). ¹ H NMR (400 MHz, DMSO -d ₆ -D ₂ O) δ ppm. 7.78 (d, J = 9.0 Hz, 1H), 7.08 (t, J = 1.9 Hz, 1H), 6.98 (dd, J = 9.2, 2.4 Hz, 1H), 6.95 (s, 1H), 4.10 (s, 2H), 4.02 (t, J = 5.6 Hz, 2H), 3.33 (t, J = 5.5 Hz, 2H), 1.34 (s, 9H); MS (APCI ⁺ ) m/z 397.3 [MC(O)OC(CH ₃ ) ₃ +CH ₃ CN+H] ⁺ .

Example 217C: tert-Butyl (2-{[5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]oxy}ethyl)carbamate, ammonium salt

[00813] In a Parr shaker, 10% palladium on carbon (0.16 g, 0.057 mmol, 50 wt % in water) was added to a solution of the product from Example 217B (0.0772 g, 0.169 mmol) in trifluoroethanol (2 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (4 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. ^Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to ₇ with dry ice) at 206 nM to give the title compound (34.8 mg, 0.073 mmol, 43.1% yield). ¹ H NMR (600 MHz, DMSO- d6 ) δ ppm. 9.31 (br. s, 1H), 6.75 (t, J = 5.6 Hz, 1H), 6.42 (s, 1H), 4.07 (s, 2H), 3.76-3.67 (m, 1H), 3.47 (dt, J = 9.7, 6.2 Hz, 1H), 3.42 (dt, J = 9.7, 6.0 Hz, 1H), 3.05 (k, J =6.0 Hz, 2H), 2.89 (dd, J =16.9, 4.5 Hz, 1H), 2.62 (td, J =18.3, 17.2, 6.5 Hz, 2H), 2.56-2.47 (m, 1H), 1.87 (s, 1H), 1.73 (dk, J =13.3, 7.1 Hz, 1H), 1.37 (s, 9H); MS (IER ^- ) m/z 458 [MH] ^- .

Example 218: 5-(1-fluoro-3-hydroxy-6-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 317)

Example 218A: 5-[3-(benzyloxy)-1-fluoro-6-methoxynaphthalene-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00814] To the vial were added 5-[3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 210G, 0.075 g, 0.16 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.007 g, 0.008 mmol), di- tert -butyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (0.009 g, 0.02 mmol), and cesium carbonate (0.110 g, 0.338 mmol). The vial was sealed, evacuated, and backfilled with nitrogen. The pump/fill cycle was repeated three more times. A solution of methanol (0.039 mL, 0.97 mmol) in degassed dimethylacetamide (0.40 mL) was then added. The vial was heated to 60 °C. After 14 h, the vial was cooled to ambient temperature and the reaction mixture was partitioned between 1 M hydrochloric acid (25 mL) and ethyl acetate (25 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [60 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to afford the title compound as the corresponding ammonium salt (0.046 g, 0.11 mmol, 66% yield). ¹ H NMR (500 MHz, DMSO -d ₆ ) δ ppm. 7.84 (d, J =9.1 Hz, 1H), 7.59-7.52 (m, 2H), 7.40-7.34 (m, 2H), 7.33-7.28 (m, 1H), 7.26-7.22 (m, 2H), 7.11 (lat s, 3H), 7.09 (dd, J =9.1, 2.4 Hz, 1H), 5.25 (s, 2H), 4.07 (s, 2H), 3.87 (s, 3H); MS (CIAD ⁺ ) m/z 417.0 [M+H] ⁺ .

Example 218B: 5-(1-fluoro-3-hydroxy-6-methoxynaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00815] A vial containing a suspension of the product from Example 218A (0.083 g, 0.19 mmol) and 1,2,3,4,5-pentamethylbenzene (0.085 g, 0.57 mmol) in dichloromethane (1.9 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (1.5 mL, 1.5 mmol) was then added. The resulting mixture was stirred at -78 °C for 10 min, then the dry ice-acetone bath was replaced with an ice/water bath. After 1 hour, the vial was recooled to -78 °C. The reaction mixture was diluted with dichloromethane (3 mL) and quenched by the successive addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was allowed to warm to ambient temperature and stirred for 15 min before concentration under reduced pressure. The residue was co-evaporated with ethanol (2 x 5 mL) and purified by reverse phase chromatography [120 g Agela Claricep™ C18 100 40-60 μm, gradient of methanol in water 10-100% (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound as the corresponding ammonium salt (0.052 g, 0.15 mmol, 79% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 7.77 (d, J = 9.1 Hz, 1H), 7.58 (br s, 3H), 7.13 (t, J = 1.8 Hz, 1H), 6.99 (dd, J = 9.1, 2.5 Hz, 1H), 6.97 (s, 1H), 4.07 (s, 2H), 3.84 (s, 3H); MS (IER ^- ) m/z 325.0 (MH) ^- .

Example 218C: 5-(1-fluoro-3-hydroxy-6-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00816] In a Parr shaker, 10% palladium on carbon (0.0582 g, 0.0829 mmol, 50 wt % in water) was added to a solution of the product from Example 218B (0.0582 g, 0.178 mmol) in trifluoroethanol (7.1 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (4 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. ^Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice) at 206 nM to give the title compound as the corresponding ammonium salt (24.3 mg, _0.070 mmol, 39.2% yield). ¹ H NMR (600 MHz, DMSO- d6 ) δ ppm. 8.96 (br s, 1H), 7.13 (br s, 4H), 6.41 (d, J = 1.4 Hz, 1H), 3.93 (s, 2H), 3.63-3.55 (m, 1H), 3.28 (s, 3H), 2.88 (dd, J = 16.7, 4.4 Hz, 1H), 2.67-2.55 (m, 2H), 2.56-2.46 (m, 1H), 1.95-1.85 (m, 1H), 1.73 (dk, J = 13.6, 7.1 Hz, 1H); MS (IER ^- ) m/z 329 [MH] ^- .

Example 219: 5-{6-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 318)

Example 219A: 5-{3-(benzyloxy)-6-[(cyclopropylmethyl)amino]-1-fluoronaphthalene-2-yl}-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00817] 5-[3-(benzyloxy)-6-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Example 210G, 0.150 g, 0.322 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.015 g, 0.016 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (0.009 g, 0.02 mmol) were added to the vial. and cesium carbonate (0.315 g, 0.967 mmol). A solution of cyclopropylmethanamine (0.046 g, 0.65 mmol) in degassed N,N -dimethylformamide (1.6 mL) was added and the flask was heated to 80 °C. After 2 h, the flask was cooled to ambient temperature and the reaction mixture was partitioned between 1 M hydrochloric acid (40 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% acetonitrile gradient in water (buffered with 0.1% trifluoroacetic acid)] to afford the title compound as the corresponding trifluoroacetic acid salt (0.149 g, 0.261 mmol, 81% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 7.69 (d, J =9.0 Hz, 1H), 7.53-7.46 (m, 2H), 7.42-7.35 (m, 2H), 7.35-7.29 (m, 1H), 7.09 (s, 1H), 7.00 (dd, J =9.0, 2.1 Hz, 1H), 6.72 (s, 1H), 5.21 (s, 2H), 4.50 (s, 2H), 3.01 (d, J =6.7 Hz, 2H), 1.21-1.00 (m, 1H), 0.58-0.45 (m, 2H), 0.33-0.20 (m, 2H); MS (ESI ⁺ ) m/z 455.7 [M+H] ⁺ .

Example 219B: 5-{6-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00818] A vial containing a suspension of the product from Example 219A (0.142 g, 0.249 mmol) and 1,2,3,4,5-pentamethylbenzene (0.111 g, 0.748 mmol) in dichloromethane (2.5 mL) was cooled to -78 °C with stirring under nitrogen. Trichloroborane (1.0 M in dichloromethane) (2.0 mL, 2.0 mmol) was then added. The resulting mixture was stirred at -78 °C for 10 min, then the dry ice-acetone bath was replaced with an ice/water bath. After 1 h, the vial was recooled to -78 °C. The reaction mixture was diluted with dichloromethane (3 mL) and quenched by the sequential addition of ethyl acetate (3 mL) and ethanol (3 mL). The mixture was allowed to warm to ambient temperature and stirred for 15 min before concentration under reduced pressure. The residue was co-evaporated with ethanol (2 x 5 mL) and purified by reverse phase chromatography [120 g ^Biotage® Sfär C18 Duo 100 Å 30 μm column, 10-100% gradient of methanol in water (buffered with 0.1% trifluoroacetic acid)] to afford the title compound as the corresponding trifluoroacetic acid salt (0.093 g, 0.19 mmol, 78% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm. 10.28 (broad s, 1H), 7.62 (d, J =9.1 Hz, 1H), 6.92 (dd, J =9.1, 2.1 Hz, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 4.45 (s, 2H), 2.99 (d, J =6.7 Hz, 2H), 1.16-1.03 (m, 1H), 0.53-0.47 (m, 2H), 0.28-0.23 (m, 2H); MS (CIAD ⁺ ) m/z 366.3 [M+H] ⁺ .

Example 219C: 5-{6-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00819] In a Parr shaker, 10% palladium on carbon (0.0674 g, 0.0960 mmol, 50 wt % in water) was added to a solution of the product from Example 219B (0.0674 g, 0.140 mmol) in trifluoroethanol (5.6 mL). The reactor was purged with nitrogen and then stirred under hydrogen (120 psi) at 25 °C until all hydrogen was consumed (5 days). The reactor was purged with nitrogen and the crude reaction mixture was filtered, washing the solid with methanol. ^Celite® (1 g) was added to the filtrate and the resulting mixture was then concentrated in vacuo to give a solid which was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M aqueous ammonium bicarbonate, pH adjusted to ₇ with dry ice) at 206 nM to give the title compound (24.8 mg, 0.067 mol, 47.8% yield). ¹ H NMR (500 MHz, DMSO- d6 ) δ ppm. 9.16 (lat s, 1H), 8.47 (lat s, 2H), 6.47 (s, 1H), 3.93 (s, 2H), 3.07 (dd, J =16.4, 5.0 Hz, 1H), 2.97-2.85 (m, 2H), 2.83-2.76 (m, 1H), 2.71 (dd, J =16.4, 10.0 Hz, 1H), 2.56 (td, J =10.9, 5.3 Hz, 1H), 2.20 (d, J =10.0 Hz, 1H), 1.68 (cd, J =11.3, 5.6 Hz, 1H), 1.04 (tt, J =7.6, 4.6 Hz, 1H), 0.63-0.56 (m, 2H), 0.39-0.32 (m, 2H); MS (ESI ⁺ ) m/z 370 [M+H] ⁺ .

Example 220: 5-[6-(2-aminoethoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 319)

[00820] To a suspension of the product from Example 217 (11.6 mg, 0.0240 mmol) in 1,2-dichloroethane (0.45 mL) was added trifluoroacetic acid (0.090 mL, 1.168 mmol). After 1 h, the reaction mixture was sonicated for 2 min and then stirring was continued. After 2 h, the reaction mixture was sonicated for 2 min and then diluted with methanol (0.5 mL) and acetonitrile (0.5 mL). The resulting solution was concentrated, the residue was dissolved in a 1:1 mixture of methanol/acetonitrile (1 mL), ^Celite® (1 g) was added, and the resulting mixture was concentrated under reduced pressure to give a powder. The solid was loaded dry onto a Teledyne ISCO 50 g reverse phase C18 column and eluted with a gradient of 10 to 100% methanol in buffer (0.025 M ammonium bicarbonate in water, pH adjusted to 7 with dry ice) to give the title compound (5.9 mg, 0.016 mmol, 67.3% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 7.73 (br s, 4H), 6.43 (s, 1H), 3.95 (d, J =13.1 Hz, 1H), 3.91 (d, J = 13.1 Hz, 1H), 3.83-3.75 (m, 1H), 3.66 (dt, J =10.4, 5.2 Hz, 1H), 3.60 (dt, J =10.5, 5.2 Hz, 1H), 3.00-2.89 (m, 3H), 2.68 (dk, J =19.8, 7.0, 6.5 Hz, 2H), 2.59-2.50 (m, 1H), 1.92-1.80 (m, 2H); MS (CIAD ⁺ ) m/z 360 [M+H] ⁺ .

Example 221: 5-{2-[2-(3,5-dimethyl-1H- pyrazol -4-yl)ethyl]-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 320)

Example 221A: Ethyl 2-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetate

[00821] To a solution of the product from Example 127B (450 mg, 2.470 mmol) and Cs ₂ CO ₃ (1609 mg, 4.94 mmol) in acetonitrile (5 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl, 0.657 mL, 3.70 mmol) dropwise at 0 °C. The mixture was stirred at 20 °C under N ₂ for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (630 mg, 2.02 mmol, yield 82%). MS (ESI ⁺ ) m/z 313 [M+H] ⁺ .

Example 221B: 2-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethanol

[00822] The title compound was prepared from the product of Example 221A using the procedures described for Example 127D in 98% yield. MS (ESI ⁺ ) m/z 271 [M+H] ⁺ .

Example 221C: 2-(3,5-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetaldehyde

[00823] The title compound was prepared from the product of Example 221B using the procedures described for Example 127E in 55% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm -0.10-0.02 (m, 9H), 0.80-0.95 (m, 2H), 2.18 (s, 3H), 2.21-2.31 (m, 3H), 3.42 (d, J= 2.38 Hz, 2H), 3.49-3.62 (m, 2H), 5.19-5.44 (m, 2H), 9.58 (t, J= 2.31 Hz, 1H).

Example 221D: 5-{6-(benzyloxy)-2-[2-(3,5-dimethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethyl]-4,4,8-trifluoro-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00824] The title compound was prepared using the procedures described for Example 127Q from the product from Example 221C in 53.2% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm -0.05 (s, 9H), 0.73-0.92 (m, 3H), 1.01 (br s, 3H), 1.16-1.39 (m, 3H), 1.96 (br s, 3H), 2.50 (br s, 4H), 2.77-3.06 (m, 2H), 3.50-3.57 (m, 2H), 4.22 (br s, 2H), 4.96 (br s, 2H), 5.25 (br s, 2H), 6.73-7.26 (m, 6H).

Example 221E: 5-{2-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-4,4,8-trifluoro-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-7-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00825] The title compound was prepared using the procedures described for Example 127R from the product from Example 221D in 25.4% yield. ¹ H NMR (400 MHz, methanol- d4 ) δ ppm 2.20 (s, 6H), 2.49-2.79 (m, 4H), 3.15 (br t, J= 11.82 Hz, 2H), 3.72 (s, 2H), 4.30 (s, 2H), 6.89-7.09 (m, 1H), 7.00 (s, 1H); MS (ESI ^- ) m/z 458 [MH] ^- .

Example 222: N -(cyclohexylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide (Compound 321)

Example 222A: 6-(benzyloxy)-N-(cyclohexylmethyl)-8-fluoro-7-(1,1,4-trioxo- ^1λ6,2,5 -thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00826] The title compound was prepared from cyclohexylmethanamine using the procedures described for Example 159A. MS (APCI ⁺ ) m/z 531.2 [M+H] ⁺ .

Example 222B: N-(cyclohexylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[00827] The title compound was prepared from Example 222A above using the procedures described for Example 159B in 33% yield (for 2 steps). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 7.06 (s, 3H), 6.60 (t, J = 5.6 Hz, 1H), 6.49 (d, J = 1.2 Hz, 1H), 4.35 (s, 2H), 3.94 (s, 2H), 3.50 (t, J = 5.8 Hz, 2H), 2.88 (t, J = 7.0 Hz, 2H), 2.65 (t, J =5.8 Hz, 2H), 1.68-1.56 (m, 6H), 1.41 (m, 1H), 1.13 (m, 2H), 0.82 (m, 2H); MS (CIAD ⁺ ) m/z 441.2 [M+H] ⁺ .

Example 223: N -[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide (Compound 322)

Example 223A: 5-[7-amino-3-(benzyloxy)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione

[00828] To a solution of 5-[3-(benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (0.2 g, 0.495 mmol, Example 67F) in methanol (5 mL) was added ammonium acetate (1.8 g, 23.35 mmol) at room temperature. After 1 h, NaBH ₃ CN (0.047 g, 0.742 mmol) was added to the suspension. The mixture was stirred at room temperature for 18 h before diluting it with N,N -dimethylformamide and purified by preparative HPLC on a ^{Phenomenex® Luna®} 10 μm C18 column (30 mm×250 mm) eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/min (0-1 min 10% A, 1-20 min linear gradient 10-90%) to give the title compound as the trifluoroacetic acid salt (85 mg, 0.164 mmol, 33.1% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 7.99 (d, J =5.3 Hz, 3H), 7.51-7.45 (m, 2H), 7.39-7.32 (m, 2H), 7.34-7.27 (m, 1H), 6.79 (s, 1H), 5.13 (s, 2H), 4.09 (s, 2H), 3.46 (m, 1H), 3.05 (dd, J =16.3, 5.5 Hz, 1H), 2.84 (m, 2H), 2.55 (d, J =9.6 Hz, 1H), 2.07 (m, 1H), 1.72 (m, 1H); MS (CIAD ⁺ ) m/z 406.1 [M+H] ⁺ .

Example 223B: N-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide

[00829] To a suspension of the product from Example 223A (43 mg, 0.106 mmol) and triethylamine (53.7 mg, 0.530 mmol) in tetrahydrofuran-dichloromethane (2:1 ratio, 1 mL) at 23 °C was added acetic anhydride (21.65 mg, 0.212 mmol) at 23 °C to form a solution. The mixture was stirred at 23 °C for 0.5 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 1-10% methanol in dichloromethane to give the title compound as the triethylamine salt (46 mg, 0.084 mmol, 79% yield). ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 7.53-7.47 (m, 2H), 7.38-7.30 (m, 2H), 7.30-7.22 (m, 1H), 6.69 (d, J = 1.6 Hz, 1H), 5.13 (s, 2H), 4.56 (s, 2H), 4.28 (d, J = 14.0 Hz, 1H), 4.22 (d, J = 14.0 Hz, 1H), 4.07 (m, 1H), 3.19 (q, J = 7.3 Hz, 6H), 3.01 (dd, J = 16.6, 5.6 Hz, 1H), 2.86 (dd, J = 7.5, 5.4 Hz, 2H), 2.49 (dd, J = 16.6, 8.8 Hz, 1H), 1.99 (m, 1H), 1.95 (s, 3H), 1.72 (m, 1H), 1.30 (t, J =7.3 Hz, 9H).

Example 223C: N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ^6,2,5 -thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalene- 2-yl]acetamide

[00830] A mixture of the above product from Example 223B, N- [6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]acetamide, triethylamine (73 mg, 0.133 mmol), and 5% Pd/C (72 mg) in tetrahydrofuran (4 mL) was stirred under hydrogen atmosphere (80 psi) at room temperature for 2.5 hours. The crude reaction mixture was filtered through a pad of diatomaceous earth and concentrated. The residue was purified by chromatography on silica gel eluting with 1-10% methanol in dichloromethane to give the title compound (50 mg, 0.11 mmol, 82% yield) as the triethylamine salt. ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 9.02 (s, 1H), 8.86 (s, 1H), 7.92 (d, J =7.2 Hz, 1H), 6.43 (d, J =1.3 Hz, 1H), 3.96-3.86 (m, 3H), 3.09 (k, J =7.3 Hz, 6H), 2.85-2.79 (m, 1H), 2.78-2.64 (m, 2H), 2.34 (dd, J = 16.4, 8.8 Hz, 1H), 1.89-1.83 (m, 1H), 1.82 (s, 3H), 1.57 (m, 1H), 1.17 (t, J = 7.3 Hz, 9H); MS (CIAD ⁺ ) m/z 358.5 [M+H] ⁺ .

[00831] An aliquot (25 mg) of the triethylamine salt product obtained above was purified by preparative HPLC on Phenomenex ^® Luna ^® 10 µm C18 columns (30 mm x 250 mm), eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/minute (0-1 minute 5% A, 1-20 minutes linear gradient 10-50%) to give the title compound as the free base (15 mg). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm. 9.97 (s, 1H), 7.93 (d, J =7.2 Hz, 1H), 6.48 (s, 1H), 4.31 (s, 2H), 3.93-3.86 (m, 1H), 2.84 (dd, J =16.4, 5.6 Hz, 1H), 2.81-2.66 (m, 2H), 2.35 (dd, J =16.3, 8.8 Hz, 1H), 1.89-1.83 (m, 1H), 1.82 (s, 3H), 1.64-1.53 (m, 1H); MS (CIAD ^- ) m/z 356.4 [MH] ^- .

Example 224: 5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione (Compound 323)

Example 224A: 5-[3-(benzyloxy)-1-fluoro-7-(4-methylpent-1-yn-1-yl)naphthalen-2-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione, ammonium salt

[00832] To a 20 mL pressure release vial were added the product of Example 1G (0.500 g, 1.08 mmol), [1,1'-bis(di- tert -butylphosphino)ferrocene]dichloropalladium(II) (0.021 g, 0.032 mmol), and copper(I) iodide (0.020 g, 0.11 mmol). The vial was capped, evacuated, and backfilled with nitrogen. N,N -dimethylformamide (5 mL), triethylamine (1.50 mL, 10.8 mmol), and 4-methyl-1-pentyne (0.253 mL, 2.15 mmol) were then added. The vial was evacuated and backfilled with nitrogen five times and then heated to 60 °C. After 26 h, the vial was cooled to ambient temperature. Additional [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.021 g, 0.032 mmol) and copper(I) iodide (0.020 g, 0.11 mmol) were added. The vial was evacuated and backfilled with nitrogen three times, then additional 4-methyl-1-pentyne (0.253 mL, 2.15 mmol) was added. The vial was again heated to 60°C. Forty-one hours later, the vial was cooled to ambient temperature and the reaction was quenched with 1 M sodium hydrogen sulfate (15 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined, washed with brine/1 M hydrochloric acid (4:1 v/v) (5 mL), dried over sodium sulfate, and filtered. The filtrate was loaded onto diatomaceous earth (2 g), concentrated under reduced pressure and purified using reverse phase chromatography [100 g Isco Redi Sep Rf ^Gold® C18 column, gradient of 10-100% methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.223 g, 0.462 mmol, 43% yield). MS (ESI ^- ) m/z 465.0 [MH] ^- .

Example 224B: 5-(1-fluoro-3-hydroxy-7-(4-methylpentyl)-5,6,7,8-tetrahydronaphthalene-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide, ammonium salt

[00833] To a 20 mL Barnstead Hast C reactor containing 10% palladium hydroxide on carbon (0.44 g, 1.6 mmol) was added 5-[3-(benzyloxy)-1-fluoro-7-(4-methylpent-1-yn-1-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt (0.223 g, 0.462 mmol) and 2,2,2-trifluoroethanol (10 mL). The resulting mixture was stirred at 35 °C for 20 h under 56 psi of hydrogen. The catalyst was then removed by filtration and washed with methanol. The filtrate was loaded onto diatomaceous earth (2 g), concentrated under reduced pressure and purified using reverse phase chromatography [100 g Isco RediSep Rf Gold® C18 column, gradient of 10-100% methanol in water (buffered with 0.025 M aqueous ammonium bicarbonate, pH adjusted to 7 with dry ice)] to give the title compound (0.0987 g, 0.246 mmol, 53% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm. 8.92 (lat s, 1H), 7.09 (lat s, 4H), 6.41 (d, J =1.3 Hz, 1H), 3.93 (d, J =1.0 Hz, 2H), 2.75-2.58 (m, 3H), 2.04 (dd, J =16.5, 10.4 Hz, 1H), 1.85-1.79 (m, 1H), 1.61-1.50 (m, 2H), 1.40-1.29 (m, 4H), 1.25 (dtd, J = 12.7, 11.0, 5.6 Hz, 1H), 1.20-1.13 (m, 2H), 0.87 (d, J = 6.6 Hz, 6H); MS (CIAD ⁺ ) m/z 402.4 [M+NH ₄ ] ⁺ .

Example 225: 5-(8-fluoro-6-hydroxy-2-{[(2 S )-5-oxopyrrolidin-2-yl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 324)

Example 225A: 5-[6-(benzyloxy)-8-fluoro-2-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00834] A suspension of the product from Example 54A (nominal 0.315 mmol, 1 equivalent), potassium carbonate (218 mg, 1.58 mmol, 5.0 equivalents), and ( S )-5-(bromomethyl)pyrrolidin-2-one (79 mg, 0.44 mmol, 1.4 equivalents) in acetonitrile (1.00 mL, ~0.3 M) was sealed in a 1 dram vial. The sealed reaction vessel was placed in a heating block preheated to 70 °C. The reaction mixture was stirred for 20 h at 70 °C. The product mixture was cooled to 23 °C. The cooled product mixture was carefully poured into a stirred mixture of aqueous hydrochloric acid (3 M, 5 mL), water (10 mL), and ethyl acetate (15 mL). The mixture was stirred for 10 min at 23°C. The mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×10 mL). The aqueous layer was concentrated. The resulting solid residue was triturated with methanol (5×6 mL). The supernatants were combined and filtered through a pad of diatomaceous earth (0.5 cm×1.0 cm). The filter cake was washed with methanol (3×3 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue was used without further purification in the next step. MS (APCI ^- ) m/z 487 [MH] ^- .

Example 225B: 5-(8-fluoro-6-hydroxy-2-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00835] A suspension of palladium on carbon (10 wt%, 17 mg, 0.02 mmol, 5 mol%), the product from Example 225A (nominally 0.315 mmol, 1 equivalent), and ammonium formate (60 mg, 0.95 mmol, 3.0 equivalents) in ethanol (4.0 mL) was stirred for 3 hours at 23 °C. The reaction vessel was placed in a heating block preheated to 50 °C. The reaction mixture was stirred for 2 hours at 50 °C. The reaction mixture was cooled to 23 °C. Additional palladium on carbon (10 wt%, 17 mg, 0.02 mmol, 5 mol%) and ammonium formate (72 mg, 1.14 mmol, 3.6 equivalents) were added. The reaction vessel was placed in a heating block preheated to 60 °C. The reaction mixture was stirred for 2 h at 60 °C. The product mixture was then cooled to 23 °C. The cooled mixture was filtered through a pad of diatomaceous earth (0.5 cm × 1.0 cm). The filter cake was washed with methanol (3 × 3 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue was purified by reverse-phase flash column chromatography (30 g RediSep Rf Gold® C18 column eluting with a gradient of 5-100% methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide]) to afford the title compound (55 mg, 0.14 mmol, 42% yield, three steps). 1H NMR (500 MHz, DMSO -d 6) δ ppm 10.97 (br, 1H), 9.74 (br, 1H), 8.00 (br, 1H), 6.58 (s, 1H), 4.27-4.05 (m, 2H), 3.96 (s, 2H), 3.01-2.86 (m, 1H), 2.28-2.09 (m, 3H), 1.76-1.68 (m, 1H); MS (APCI ⁺ ) m/z 399 [M+H] ⁺ .

Example 226: 5-[(3 S )-5-fluoro-7-hydroxy-3-(4-methylpentyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione (Compound 325)

Example 226A: methyl (S)-2-((tert-butoxycarbonyl)amino)pent-4-ethanoate

[00836] Iodomethane (14.5 mL, 232 mmol, 2.0 equivalents) was added to a suspension of potassium carbonate (32.1 g, 232 mmol, 2.0 equivalents) and ( S )-2-(( tert -butoxycarbonyl)amino)pent-4-enoic acid (25.0 g, 116 mmol, 1 equivalent) in acetone (465 mL, 0.25 M) at 23 °C. The reaction mixture was stirred for 24 h at 23 °C. Additional iodomethane (14.5 mL, 232 mmol, 2.0 equivalents) was added at 23 °C. The reaction mixture was stirred for 3 days at 23 °C. The product mixture was partially concentrated. The resulting residue was partitioned between water (150 mL) and ethyl acetate (400 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL). The washed organic layer was dried over magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting title compound was used without further purification in the next step. TLC R _f = 0.37 (1% acetic acid-20% ethyl acetate-heptanes, ninhydrin). 1H NMR (600 MHz, CDCl ₃ ) δ ppm. 5.73-5.65 (m, 1H), 5.15-5.10 (m, 2H), 5.02 (br, 1H), 4.40-4.36 (m, 1H), 3.73 (s, 3H), 2.58-2.42 (m, 2H), 1.43 (s, 9H).

Example 226B: methyl (S)-2-((tert-butoxycarbonyl)amino)-6-methylhept-4-ethanoate

[00837] A solution of (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro( o -isopropoxyphenylmethylene)ruthenium (282 mg, 0.45 mmol, 4.5 mol%) and the product from Example 226A (2.29 g, 10.00 mmol, 1 equivalent) in dichloromethane (100 mL) in a 500 mL round bottom flask equipped with a reflux condenser with a baffle was deoxygenated by repeated evacuation (~5 seconds) and then backfilling with nitrogen (×2). The reaction vessel was opened briefly and liquid 3-methyl-1-butene (~15.0 mL, 135 mmol, 13.5 equivalents) was added. The reaction vessel was sealed with a reflux condenser (under nitrogen) and the sealed vessel was placed in a heating block preheated to 50 °C. The reaction mixture was stirred for 20 h at 50 °C. The product mixture was then cooled to 23 °C. The cooled product mixture was concentrated. The resulting residue was purified by flash column chromatography (eluting initially with heptanes, gradually increasing to 10% [v/v] ethyl acetate-heptanes, one step) to give the title compound (<1.98 g, <73% yield). TLC Rf=0.20 (10% ethyl acetate-heptanes, p -anisaldehyde). 1H NMR (500 MHz, _CDCl3 ) δ ppm. 5.48 (dd, J =15.3, 6.7 Hz, 1H), 5.26-5.20 (m, 1H), 5.00 (lat, 1H), 4.38-4.30 (m, 1H), 3.72 (s, 3H), 2.51-2.35 (m, 3H), 1.44 (s, 9H), 0.96 (d, J =2.8 Hz, 3H), 0.95 (d, J =2.8 Hz, 3H).

Example 226C: methyl (S)-2-((tert-butoxycarbonyl)amino)-6-methylheptanoate

[00838] A suspension of the product from Example 226B (nominal 1.91 g, 7.04 mmol, 1 equivalent) and palladium on carbon (10 wt %, 533.0 mg, 0.50 mmol, 7.1 mol %) in tetrahydrofuran (14.0 mL) was stirred vigorously for 20 h under hydrogen (1 atm) in a sealed 100 mL round bottom flask at 23 °C. The product mixture was diluted with methanol (15 mL) and filtered through a pad of diatomaceous earth (2.0 cm x 4.0 cm). The filter cake was washed with methanol (3 x 5 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting title compound was used without further purification in the next step. TLC Rf = 0.24 (10% ethyl acetate-heptanes, p -anisaldehyde). 1H NMR (500 MHz, CDCl3) δ ppm 5.02-4.94 (m, 1H), 4.31-4.25 (m, 1H), 3.73 (s, 3H), 1.81-1.71 (m, 1H), 1.64-1.58 (m, 1H), 1.44 (s, 9H), 1.39-1.27 (m, 3H), 1.22-1.13 (m, 2H), 0.86 (d, J =6.1 Hz, 6H).

Example 226D: tert-butyl (S)-(1-hydroxy-6-methylheptan-2-yl)carbamate

[00839] A solution of lithium borohydride in tetrahydrofuran (2.0 M, 7.04 mL, 14.08 mmol, 2.0 equivalents) was added to a solution of the product from Example 226C (nominal 7.04 mmol, 1 equivalent) in tetrahydrofuran (50 mL, 0.14 M) at 0 °C. The reaction mixture was heated to 23 °C for 20 h. The product mixture was then diluted sequentially with saturated aqueous ammonium chloride (5 mL), water (15 mL), and ethyl acetate (60 mL) at 23 °C. The resulting biphasic mixture was stirred for 30 min. The mixture was then transferred to a separatory funnel and the resulting layers were separated. The aqueous layer was extracted with ethyl acetate (35 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (eluting with 33% ethyl acetate-heptanes) to give the title compound (983 mg, 4.01 mmol, 57% yield, four steps). ¹ H NMR (600 MHz, CDCl ₃ ) δ ppm. 4.62 (lat, 1H), 3.69-3.49 (m, 3H), 2.54 (lat, 1H), 1.44 (s, 9H), 1.41-1.13 (m, 6H), 0.88 (dd, J = 6.6, 3.5 Hz, 1H), 0.86 (d, J = 6.6 Hz).

Example 226E: tert-butyl (4S)-4-(4-methylpentyl)-2-oxo-1,2 λ ⁴ ,3-oxathiazolidine-3-carboxylate

[00840] A solution of thionyl chloride in dichloromethane (2.0 M, 2.00 mL, 4.00 mmol, 1.1 equivalents) was added dropwise to a solution of imidazole (989.3 mg, 14.53 mmol, 4.0 equivalents) and triethylamine (1.19 mL, 8.53 mmol, 2.4 equivalents) in dichloromethane (30.0 mL) at -40 °C. The reaction mixture was stirred for 10 min at -40 °C. A solution of the product from Example 226D (891 mg, 3.63 mmol, 1 equivalent) in dichloromethane (6.0 mL, total 0.1 M) was added dropwise via a syringe pump over 30 min at -40 °C. The reaction mixture was allowed to warm to 23°C over 2 days. The product mixture was diluted with saturated aqueous sodium chloride solution (8 mL). The aqueous layer was extracted with dichloromethane (15 mL). The organic layers were combined, and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (eluting with 10% ethyl acetate-heptanes) to give the title compound (599 mg, 2.05 mmol, 57% yield). TLC Rf = 0.68 (25% ethyl acetate-heptanes, cerium ammonium molybdate). 1H NMR (500 MHz, CDCl ₃ ) δ ppm. 4.81-4.70 (m, 2H), 4.04-3.95 (m, 1H), 2.14-2.04 (m, 1H), 1.75-1.63 (m, 1H), 1.53 (s, 9H), 1.35-1.15 (m, 4H), 0.92-0.85 (m, 1H), 0.87 (dd, J = 6.6, 3.0 Hz, 6H); MS (APCI ⁺ ) m/z 309 [M+NH4] ⁺ .

Example 226F: tert-butyl (S)-4-(4-methylpentyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

[00841] Ruthenium(III) chloride hydrate (4.6 mg, 0.02 mmol, 1.0 mol %) and sodium periodate (659.0 mg, 3.08 mmol, 1.5 equivalents) were added sequentially to a solution of the product from Example 226E (599.0 mg, 2.06 mmol, 1 equivalent) in 20% water-acetonitrile (v/v, 7 mL, 0.29 M) at 23 °C. The reaction mixture was stirred for 10 min at 23 °C. The product mixture was then diluted with ethyl acetate (15 mL). The diluted mixture was filtered through a pad of diatomaceous earth (5.0 cm x 3.0 cm). The filter cake was washed with ethyl acetate (3 x 15 mL). The filtrates were combined. The combined filtrates were transferred to a separatory funnel and washed with saturated aqueous sodium thiosulfate solution (15 mL). The aqueous layer was extracted with ethyl acetate (15 mL). The organic layers were combined, and the combined organic layers were washed successively with saturated aqueous sodium thiosulfate solution (10 mL) and saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of diatomaceous earth (5.0 cm × 3.0 cm). The filter cake was washed with ethyl acetate (3 × 15 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue was dissolved in ether (3 mL) and filtered through a pad of silica gel (0.5 cm × 3.0 cm). The filter cake was washed with ether (3 × 2 mL). The filtrates were combined and the combined filtrates were concentrated to give the title compound (584 mg, 1.90 mmol, 92% yield). TLC Rf=0.43 (20% ethyl acetate-heptanes, cerium ammonium molybdate). 1H NMR (600 MHz, CDCl3) δ ppm. 4.63 (ddd, J =9.2, 5.9, 0.8 Hz, 1H), 4.32-4.22 (m, 2H), 1.94-1.84 (m, 1H), 1.83-1.72 (m, 1H), 1.55 (s, 9H), 1.39-1.26 (m, 2H), 1.26-1.17 (m, 2H), 0.91 (d, J =6.6 Hz, 1H), 0.87 (dd, J =6.6, 3.7 Hz, 6H); MS (CIAD ⁺ ) m/z 325 [M+NH ₄ ] ⁺ .

Example 226G: tert-butyl {(2S)-1-[4-(benzyloxy)-6-bromo-2-fluoro-3-(2,2,2-trifluoroacetamido)phenyl]-6-methylheptan-2-yl}carbamate

[00842] A solution of n -butyl lithium in hexane (1.91 M, 2.08 mL, 3.96 mmol, 2.1 equivalents) was added to a solution of diisopropylamine (0.59 mL, 4.15 mmol, 2.2 equivalents) in tetrahydrofuran (8.0 mL) at -78 °C. The reaction mixture was stirred for 10 min at -78 °C. A solution of the product from Example 12C (777.0 mg, 1.98 mmol, 1.05 equivalents) in tetrahydrofuran (3.0 mL) was added dropwise via syringe pump over 20 min at -78 °C. The reaction mixture was stirred for 30 min at -78 °C. A solution of the product from Example 226F (580.0 mg, 1.89 mmol, 1 equivalent) in tetrahydrofuran (3.0 mL; 0.14 M total) was added dropwise over 20 min at 78 °C. The reaction mixture was stirred for 30 min at -78 °C. Aqueous hydrochloric acid (3 M, 3.14 mL, 9.43 mmol, 5.0 equivalents) was added at -78 °C. The resulting mixture was warmed to 23 °C over 30 min. The product mixture was diluted with ethyl acetate (30 mL). The resulting biphasic mixture was then transferred to a separatory funnel and the layers were separated. The organic layer was washed with saturated aqueous sodium chloride solution (5 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The resulting title compound was used without further purification in the next step. MS (APCI ⁺ ) m/z 619 [M+H] ⁺ .

Example 226H: methyl {[6-(benzyloxy)-4-bromo-3-{(2S)-2-[(tert-butoxycarbonyl)amino]-6-methylheptyl}-2-fluorophenyl](trifluoroacetyl)amino}acetate

[00843] Methyl bromoacetate (0.18 mL, 1.98 mmol, 1.1 equivalents) was added to a suspension of the product from Example 226G (nominal 1.89 mmol, 1 equivalent), potassium carbonate (782 mg, 5.66 mmol, 3.0 equivalents), and potassium iodide (157 mg, 0.94 mmol, 0.5 equivalents) in acetone (9.5 mL, 0.2 M) at 23 °C. The reaction mixture was stirred for 65 h at 23 °C. The product mixture was concentrated under a stream of nitrogen. The resulting residue was partitioned between ethyl acetate (20 mL), water (3 mL), and saturated aqueous ammonium chloride (5 mL). The organic layer was washed with saturated aqueous sodium chloride (3 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (~5 g) was added to the solution and the mixture was concentrated. The resulting residue was purified by flash column chromatography (40 g RediSep Rf Gold ^® silica gel column, eluting with a gradient of 0-60% ethyl acetate-heptanes) to afford the title compound (945 mg, 1.37 mmol, 72% yield, two steps). MS (APCI ⁺ ) m/z 591 [M+HC(O)OC(CH ₃ ) ₃ ] ⁺ .

Example 226I: methyl {[6-(benzyloxy)-3-{(2S)-2-[(tert-butoxycarbonyl)amino]-6-methylheptyl}-4-ethenyl-2-fluorophenyl](trifluoroacetyl)amino}acetate

[00844] A suspension of cesium carbonate (890 mg, 2.73 mmol, 2.0 equivalents), potassium vinyl trifluoroborate (366 mg, 2.73 mmol, 2.0 equivalents), bis(triphenylphosphine) palladium(II) dichloride (48.0 mg, 0.07 mmol, 5.0 mol %), and the product from Example 226H (945 mg, 1.37 mmol, 1 equivalent) in 20% aqueous dioxane (v/v, 11.0 mL, 0.15 M) in a 20 mL scintillation vial fitted with a screw cap with a septum. The sealed reaction mixture was deoxygenated by repeated evacuation (~5 seconds) and subsequent backfill with nitrogen (×3). The reaction vessel was placed in a heating block preheated to 80 °C. The reaction mixture was stirred for 1.5 h at 80 °C. The reaction mixture was then heated to 100 °C. The reaction mixture was stirred for 3 h at 100 °C. The product mixture was then cooled to 23 °C. The cooled product mixture was filtered through a pad of diatomaceous earth (3.0 cm × 1.0 cm). The filter cake was washed with ethyl acetate (3 × 15 mL). The filtrates were combined, and the combined filtrates were concentrated. The resulting residue was partitioned between ethyl acetate (50 mL) and water (10 mL). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (~5 g) was added to the solution, and the mixture was concentrated. The resulting residue was purified by flash column chromatography (40 g RediSep Rf Gold ^® silica gel column, eluting with a gradient of 0-60% [v/v] ethyl acetate-heptanes). The resulting title compound (623 mg, <71% yield) was used without further purification in the next step. MS (APCI ⁺ ) m/z 538 [MC(O)OC(CH ₃ ) ₃ +H] ⁺ .

Example 226J: methyl {[6-(benzyloxy)-3-{(2S)-2-[(tert-butoxycarbonyl)amino]-6-methylheptyl}-2-fluoro-4-formylphenyl](trifluoroacetyl)amino}acetate

[00845] A solution of N -methylmorpholine N -oxide in water (50% w/v, 0.69 mL, 2.93 mmol, 3.0 equivalents) was added to a suspension of potassium osmate dihydrate (14.0 mg, 0.04 mmol, 4.0 mol %) and the product of Example 226I (623 mg, 0.98 mmol, 1 equivalent) in 25% water-tetrahydrofuran (v/v, 10 mL, ~0.1 M) at 23 °C. The reaction mixture was stirred for 18 h at 23 °C. Sodium metaperiodate (209 mg, 0.975 mmol, 1.0 equivalent) was added in one portion at 23 °C. The reaction mixture was stirred for 6 h at 23 °C. Additional sodium metaperiodate (187 mg, 0.86 mmol, 0.89 equivalents) was added in one portion at 23 °C. The reaction mixture was stirred for 30 min at 23 °C. The product mixture was then diluted sequentially with saturated aqueous sodium thiosulfate (10 mL), water (5 mL), and ethyl acetate (50 mL). The diluted mixture was stirred for 15 min at 23 °C. The resulting biphasic mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 25 mL). The organic layers were combined, and the combined organic layers were washed sequentially with saturated aqueous sodium thiosulfate (10 mL) and saturated aqueous sodium chloride (15 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The title compound was used in the next step without further purification. MS (APCI ⁺ ) m/z 541 [MS(O)OC(CH ₃ ) ₃ +H] ⁺ .

Example 226K: tert-butyl (3S)-7-(benzyloxy)-5-fluoro-6-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-3-(4-methylpentyl)-3,4-dihydroisoquinoline-2(1H) -carboxylate

[00846] Triethylsilane (0.86 mL, 5.36 mmol, 5.5 equivalents) and boron trifluoride diethyl etherate (0.62 mL, 4.8 mmol, 5.0 equivalents) were added dropwise sequentially to a solution of the product from Example 226J (nominally 0.98 mmol, 1 equivalent) in dichloromethane (10.0 mL) at -78 °C. The reaction mixture was stirred for 45 min at -78 °C. The product mixture was then diluted sequentially with saturated aqueous sodium bicarbonate (4 mL) and water (1 mL). The diluted mixture was heated to 23 °C with stirring for 1 h. The resulting biphasic mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (15 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (5 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (~5 g) was added to the solution and the mixture was concentrated. The resulting residue was purified by flash column chromatography (40 g RediSep Rf Gold ^® silica gel column, eluting with a gradient of 0-25% [v/v] ethyl acetate-heptanes). Fractions containing the product were collected and concentrated. The resulting title compound (<400 mg, <66% over two steps) was used without further purification in the next step. MS (APCI ⁺ ) m/z 525 [M+HC(O)OC(CH ₃ ) ₃ ] ⁺ .

Example 226L: tert-butyl (3S)-7-(benzyloxy)-5-fluoro-6-[(2-methoxy-2-oxoethyl)amino]-3-(4-methylpentyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00847] A solution of sodium methoxide in methanol (25% w/v, 0.35 mL, 1.60 mmol, 2.5 equivalents) was added to a solution of the product from Example 226K (~400 mg, ~0.64 mmol, 1 equivalent) in anhydrous methanol (3.2 mL, 0.2 M) in a 20 mL scintillation vial fitted with a screw cap to release pressure under nitrogen at 23 °C. The sealed reaction mixture was subjected to a vacuum (~5 seconds) and then backfilled with nitrogen (×3). The sealed reaction mixture was placed in a heating block preheated to 60 °C. The reaction mixture was stirred for 10 min at 60 °C. The reaction mixture was then cooled to 23 °C. A solution of hydrogen chloride in dioxane (4 M, 0.80 mL, 3.20 mmol, 5 equivalents) was added to the cooled reaction mixture at 23 °C. The reaction mixture was stirred for 10 min at 23 °C. The product mixture was successively diluted with ethyl acetate (30 mL), water (3 mL), and saturated aqueous sodium chloride solution (5 mL). The resulting biphasic mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, and the combined organic layers were washed with saturated aqueous sodium chloride solution (7 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The resulting title compound was used without further purification in the next step. MS ( ^APCI ) m/z 529 [M+H] ⁺ .

Example 226M: tert-butyl (3S)-7-(benzyloxy)-5-fluoro-6-[(2-methoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-3-(4-methylpentyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00848] Allyl alcohol (0.05 mL, 0.74 mmol, 1.2 equivalents) was added to a solution of chlorosulfonyl isocyanate (0.06 mL, 0.69 mmol, 1.1 equivalents) in dichloromethane (3.20 mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. A solution of the product from Example 226L (nominally 0.64 mmol, 1 equivalent) and triethylamine (0.27 mL, 1.92 mmol, 3.0 equivalents) in dichloromethane (3.20 mL, total 0.1 M) was added dropwise at 0 °C. The reaction mixture was stirred for 2 h at 0 °C. The product mixture was diluted with saturated aqueous sodium chloride solution (3 mL). The resulting biphasic mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (2×5 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting title compound was used without further purification in the next step. MS (APCI ⁺ ) m/z 709 [M+NH4] ⁺ .

Example 226N: tert-butyl (3S)-7-(benzyloxy)-5-fluoro-3-(4-methylpentyl)-6-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[00849] A solution of sodium methoxide in methanol (0.5 M, 3.84 mL, 1.92 mmol, 3.0 equivalents) was added to a suspension of the product from Example 226M (nominally 0.64 mmol, 1 equivalent) and tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.03 mmol, 0.05 equivalents) in anhydrous methanol (2.0 mL, 0.32 M) under nitrogen at 23 °C. The reaction vessel (20 mL septum screw cap vent bottle) was sealed. The sealed reaction mixture was deoxygenated by repeated evacuation (~5 sec) and subsequent flushing with nitrogen (×3). The reaction vessel was placed in a heating block preheated to 60 °C. The reaction mixture was stirred for 10 min at 60 °C and then the reaction mixture was cooled to 23 °C. The cooled mixture was partitioned between aqueous hydrochloric acid (3.0 M, 2.5 mL) and ethyl acetate (15 mL). The aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (~7 g) was added to the filtrate and the mixture was concentrated. The resulting residue was purified by flash column chromatography (RediSep Rf ^Gold® silica gel column 12 g, eluting with a gradient of 0-100% acetonitrile-ethyl acetate) to give the title compound (284 mg, 0.493 mmol, 77% yield). MS (CIAD ⁺ ) m/z 593 [M+NH4] ⁺ .

Example 226O: 5-[(3S)-7-(benzyloxy)-5-fluoro-3-(4-methylpentyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1 λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione

[00850] A solution of boron trichloride in dichloromethane (1.0 M, 7.00 mL, 7.00 mmol, 14.2 equivalents) was slowly added to a solution of the product from Example 226N (nominal 0.493 mmol, 1 equivalent) and pentamethylbenzene (80 mg, 0.54 mmol, 1.1 equivalents) in dichloromethane at -78 °C. The cooling bath was immediately removed and replaced with a separate cooling bath at 0 °C. The reaction mixture was heated to 0 °C over 1 hour. The reaction mixture was cooled to -78 °C. Additional boron trichloride in dichloromethane (1.0 M, 5.00 mL, 5.00 mmol, 10.1 equivalents) was slowly added at -78 °C. The cooling bath was immediately removed and replaced with a separate cooling bath at 0 °C. The reaction mixture was heated to 0 °C over 30 min. The product mixture was cooled to -78 °C. The mixture was slowly diluted with ethanol (5.0 mL) at -78 °C. The diluted mixture was concentrated. The resulting title compound was used without further purification in the next step. MS (APCI ⁺ ) m/z 476 [M+H] ⁺ .

Example 226P: 5-[(3S)-5-fluoro-7-hydroxy-3-(4-methylpentyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-1λ6,2,5 ^- thiadiazolidine-1,1,3-trione, ammonium salt

[00851] A suspension of the product from Example 226O (nominal 0.493 mmol, 1 equivalent), palladium on carbon (10 wt %, 52 mg, 0.05 mmol, 0.1 equivalent), and ammonium formate (155 mg, 2.47 mmol, 5.0 equivalent) in ethanol (5.00 mL, ~0.1 M) was sealed in a 20 mL screw-capped pressure release vial fitted with a septum. The sealed reaction vessel was placed in a heating block preheated to 60 °C. The reaction mixture was stirred for 4 h at 60 °C. The product mixture was cooled to 23 °C. The cooled product mixture was filtered through a pad of diatomaceous earth (0.5 cm x 1.0 cm). The filter cake was washed with methanol (3 x 3 mL). The filtrates were combined and the combined filtrates were concentrated. The resulting residue was purified by reverse phase flash column chromatography (100 g RediSep Rf ^Gold® C18 column, eluting with a gradient of 5-100% methanol-0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide]) to afford the isolated starting material (18.5 mg, 8%) and the title compound (5.5 mg, 0.014 mmol, 3% yield, 2 steps). 1H NMR (600 MHz, DMSO- d 6) δ ppm 6.55 (s, 1H), 4.19 (s, 2H), 3.95 (s, 2H), 2.93 (dd, J = 16.7, 4.7 Hz, 1H), 2.46 (dd, J = 16.8, 11.1 Hz, 1H), 1.71-1.65 (m, 1H), 1.61-1.52 (m, 2H), 1.46-1.39 (m, 2H), 1.23-1.17 (m, 2H), 0.91-0.86 (m, 7H); MS (APCI ⁺ ) m/z 386 [M+H] ⁺ .

Biological tests

Abbreviations

[00852] BSA for bovine serum albumin; DMEM for Dulbecco's modified Eagle's medium; DMSO for dimethyl sulfoxide; DTT for dithiothreitol; EDTA for ethylenediaminetetraacetic acid; EGTA for ethyleneglycol bis(2-aminoethyl ester)-N ,N,N ',N' -tetraacetic acid; FBS for fetal bovine serum; HEPES for 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; IFNγ for gamma interferon; PBS for phosphate-buffered saline; PE-labeled for labeled fidoerythrin; RPMI 1640 for Roswell Park Memorial Institute 1640 medium; S-MEM for Spinner's minimum essential medium; TNFα for tumor necrosis factor alpha; and ^Tween® 20 for polyethyleneglycol sorbitan monolaurate.

Example 227: Mobility shift assay used to determine the efficacy of PTPN2 inhibitors

[00853] Compound activity was determined using the native His-tagged PTPN2 (TC45) protein (SEQ ID NO: 1) in an in vitro enzymatic reaction. The enzymatic assay used to determine activity was a mobility shift assay using a LabChip EZ Reader from Caliper Life Sciences. The enzymatic reaction was performed in assay buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM EDTA, 0.01% Tween ^® 20, and 2 mM DTT). Compounds were coated onto a white 384-well ProxiPlate™ plate (PerkinElmer, catalog #6008289) using a Labcyte Echo at various concentrations (12 points, 1:3 dilution). The enzyme (0.5 nM) was incubated with the compound for 10 min at room temperature. Then, the substrate (phosphorylated insulin receptor probe sequence: ((OG488)-(NH-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O-CH ₂ -CO)-TRDI-(PY)-ETDYYRKK-NH ₂ ) (SEQ ID NO: 2) was added to the plates at a concentration of 2 μM and incubated for another 10 min at room temperature. Finally, quencher solution (water and 4-bromo-3-(2-oxo-2-propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid) was added to the plates, which were then run on an EZ Reader (excitation 488 nm, emission 530 nm) to measure the % conversion (the amount of phosphorylated substrate that was dephosphorylated) PTPN2). Each plate contained 100% control (inhibitor: 4-bromo-3-(2-oxo-2-propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid) and 0% control (DMSO), which were used to calculate % inhibition. The % inhibition was then used to calculate IC ₅₀ values.

Example 228: Mobility Shift Assay (MSA) Used to Determine the Potency of PTPN1 Inhibitors

[00854] Compound activity was determined using native His-tagged full-length PTPN1 protein (SEQ ID NO: 3) in an in vitro enzymatic reaction. The enzymatic assay used to determine activity was a mobility shift assay using a LabChip EZ Reader from Caliper Life Sciences. The enzymatic reaction was performed in assay buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM EDTA, 0.01% Tween ^® 20, and 2 mM DTT). Compounds were dispensed onto a white 384-well ProxiPlate™ plate (PerkinElmer Cat. #6008289) using a Labcyte Echo ^® liquid handler at various concentrations (12 points, 1:3 dilution). The enzyme (0.5 nM) was incubated with the compound for 10 min at room temperature. Then, the substrate (phosphorylated insulin receptor probe sequence: ((OG488)-(NH-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O-CH ₂ -CO)-TRDI-(PY)-ETDYYRKK-NH ₂ ) (SEQ ID NO: 2) was added to the plates at a concentration of 2 μM and incubated for another 10 min at room temperature. Finally, quencher solution (water and 4-bromo-3-(2-oxo-2-propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid) was added to the plates, which were then run on an EZ Reader (excitation 488 nm, emission 530 nm) to measure the % conversion (the amount of phosphorylated substrate that was dephosphorylated) PTPN1). Each plate contained 100% control (inhibitor: 4-bromo-3-(2-oxo-2-propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid) and 0% control (DMSO), which were used to calculate % inhibition. The % inhibition was then used to calculate IC ₅₀ values.

[00855] Table 2 below summarizes IC ₅₀ data obtained using the PTPN2 MSA assay and the PTPN1 MSA assay for representative compounds of the invention. In this table, "A" represents an IC ₅₀ of less than 1 nM; "B" represents an IC ₅₀ of 1 to 10 nM; "C" represents an IC ₅₀ of greater than 10 to 100 nM; and "D" represents an IC ₅₀ of greater than 100 nM.

Table 2: IC ₅₀ values of representative compounds in the PTPN2 and PTPN1 mobility shift assays (MSA)

Connection No. PTPN2 MSA IC ₅₀ (nM) PTPN1 MSA IC ₅₀ (nM) Connection No. PTPN2 MSA IC ₅₀ (nM) PTPN1 MSA IC ₅₀ (nM) 100 C B 101 B B 102 A B 103 C 104 C C 105 B B 106 C C 107 C C 108 C C 109 C C 110 C C 111 C C 112 D D 113 D D 114 C C 115 C C 116 C C 117 C C 118 B B 119 B B 120 B B 121 B C 122 B C 123 B B 124 B B 125 B C 126 B B 127 B B 128 B B 129 B B 130 B B 131 B B 132 C C 133 B B 134 C C 135 C C 136 C C 137 A B 138 C C 139 B C 140 C C 141 B C 142 B C 143 C D 144 B C 145 C C 146 B 147 C C 148 A A 149 B C 150 B B 151 B C 152 B 153 C C 154 B C 155 C C 156 B B 157 B C 158 C D 159 C C 160 C C 161 B C 162 B C 163 C D 164 C D 165 C C 166 A B 167 B C 168 C C 169 C 170 C D 171 B B 172 C C 173 B B 174 B B 175 B C 176 C C 177 A B 178 A B 179 C C 180 C D 181 B B 182 C C 183 D D 184 D D 185 B B 186 C C 187 B B 188 C C 189 B D 190 B C 191 C C 192 C C 193 D C 194 B B 195 C C 196 C C 197 C C 198 C D 199 A A 200 A A 201 A A 202 A B 203 A B 204 A B 205 B C 206 C C 207 C C 208 C C 209 B B 210 D C 211 B B 212 D D 213 D D 214 C C 215 D D 216 D D 217 D D 218 D C 219 C C 220 C C 221 C B 222 C C 223 C B 224 D C 225 B C 226 C C 227 D D 228 D C 229 C C 230 D C 231 C B 232 D C 233 D C 234 C B 235 C C 236 D C 237 D D 238 B B 239 B B 240 C D 241 C C 242 C C 243 B B 244 C C 245 C C 246 C C 247 C C 248 C C 249 C C 250 C C 251 C C 252 D D 253 B B 254 C C 255 D C 256 B B 257 B B 258 B B 259 C C 260 B B 261 C C 262 C B 263 C 264 C C 265 C 266 B B 267 C 268 C C 269 B B 270 C C 271 C C 272 C C 273 B B 274 B B 275 C C 276 A B 277 B C 278 C C 279 C C 280 D D 281 C C 282 C C 283 C D 284 C C 285 C 286 B B 287 C D 288 C B 289 C D 290 B B 291 B B 292 C C 293 C C 294 C C 295 C D 296 C D 297 A B 298 C C 299 B C 300 B B 301 C D 302 B C 303 B 304 D D 305 C C 306 D D 307 B B 308 B B 309 C C 310 C C 311 B B 312 C C 313 B C 314 C D 315 B C 316 C D 317 C D 318 B C 319 C D 320 D D 321 B B 322 C 323 B 324 B 325 B

Example 229: Assay for inhibition of cell growth induced by IFN γ B16F10

[00856] B16F10 mouse melanoma cells (ATCC Cat# CRL-6475, Manassas, VA) were seeded at a density of 500 cells per well in a 384-well clear bottom plate (Corning Cat# 3765, Corning, NY) in a total volume of 25 µl DMEM+10% FBS (Sigma Cat# D6429 and Sigma Cat# F4135, St. Louis, MO). Cells were allowed to attach overnight at 37°C+5% _CO2 . The following day, 12.5 μL of mouse IFNγ (RD Systems, Cat#485-MI/CF, Minneapolis, MN) at 2 ng/mL was added to half the plate (columns 13-24) for a final assay concentration of 0.5 ng/mL IFNγ. Medium only (12.5 μL DMEM+10% FBS) was added to the remainder of the plate (columns 1-12). Compounds resuspended in DMSO (Sigma Cat#D2650) at 100 mM were then diluted in half-log dilutions in DMSO ranging from 100 mM to 0.001 mM, and DMSO controls only were included. Compound/DMSO dilutions were further diluted 1:250 in DMEM+10% FBS, and 12.5 μl of these dilutions were added in triplicate to cells from both treatment groups (with and without IFNγ). Final compound concentrations ranged from 100 μM to 0.001 μM with a final DMSO concentration of 0.1%. Compounds were dispensed only into the inner 240 wells, avoiding the outer 2-well perimeter of the plate to minimize edge effects. Finally, the plate was loaded into the ^IncuCyte® S3 Live Cell Assay System (Essen Bioscience-Sartorius, Ann Arbor, MI) maintained in a 37°C+5% _CO2 incubator, allowed to equilibrate for 2 h, and imaged every 6 h for 5 days. Confluence was measured over time for compound dilutions in the presence and absence of IFNγ. Growth inhibition values were obtained when the DMSO/no IFNγ control reached >95% confluence. At these time points, the percent growth inhibition at each compound dose level relative to the DMSO/with IFNγ control was calculated for each compound and used to determine the IC ₅₀ .

[00857] The search for new strategies to suppress tumor growth is an active area of research in cancer drug discovery. The growth of some cancer types, including melanoma, can be suppressed by IFNγ, a cytokine produced by immune cells such as T cells or NK cells. Inhibition of IFNγ signaling promotes tumor growth. Conversely, enhancement of IFNγ signaling enhances tumor growth inhibition. Because PTPN2 and PTPN1 are negative regulators of cytokine signaling, including IFN signaling through dephosphorylation of JAK and STAT proteins, a potent compound should be able to inhibit tumor growth in the presence of IFNγ.

[00858] The compounds of the present invention enhance the inhibition of B16F10 melanoma growth in the presence of IFNγ. Importantly, tumor growth inhibition is not observed in the absence of IFNγ, indicating the mechanism of action of the compounds.

[00859] Table 3 below summarizes the IC ₅₀ values for inhibition of cell growth induced by B16F10 IFNγ for representative compounds of the present disclosure. In this table, "A" represents an IC ₅₀ of less than 1 μM; "B" represents an IC ₅₀ of 1 to 10 μM; "C" represents an IC ₅₀ of greater than 10 μM to 100 μM; and "D" represents an IC ₅₀ of greater than 100 μM.

Table 3: IC ₅₀ values of representative compounds of the invention in the B16F10 IFNγ-induced cell growth inhibition (GI) assay

Connection No. B16F10 GI IC50 (µM) Connection No. B16F10 GI IC50 (µM) 102 A 103 B 104 C 106 C 107 C 108 C 109 C 111 C 112 C 116 B 117 B 118 A 119 B 120 A 122 B 123 B 124 A 125 C 126 B 127 A 128 B 129 A 130 B 131 A 133 A 134 B 135 B 136 D 137 C 139 C 142 C 143 B 145 B 146 A 148 A 150 B 151 B 153 D 155 C 156 A 157 B 161 C 166 A 169 C 172 B 173 A 174 A 175 A 177 A 178 A 179 B 180 B 184 C 185 A 187 A 188 A 189 B 190 B 194 B 196 B 197 B 199 A 200 A 202 A 203 A 205 B 206 B 208 C 209 B 211 A 214 B 217 B 218 C 221 B 223 A 225 B 229 B 231 B 234 B 235 B 238 B 241 C 243 B 245 B 247 C 250 D 251 B 252 C 253 B 254 B 255 B 257 B 258 B 259 B 260 A 262 C 268 B 269 C 276 B 286 B 288 B 291 A 292 B 293 B 306 D 307 A 308 A

Example 230: Proximal pharmacodynamic (PD) assay of pSTAT1 in human whole blood

[00860] Human blood samples were collected from the AbbVie Inc. internal blood donor program in accordance with AbbVie Occupational Safety and Health Administration protocols. Blood was collected by venipuncture into sodium heparin-coated evacuated tubes and stored at room temperature for no more than 1 hour prior to the start of the experiment. Human blood samples (90 μL) were added to individual wells of 96-well plates containing 10 μL of a 10x working solution with increasing concentrations of compounds to achieve final concentrations ranging from 0.025 μM to 500 μM and incubated for 3 hours at 37°C. To induce STAT1 phosphorylation, samples were then treated with recombinant human IFNγ (R&D Systems, Cat. #285-IF, Minneapolis, MN; final concentration 100 nM) for 20 min and 3 μl/well of BV421-labeled anti-CD14 surface antibody (Biolegend, San Diego, CA, Cat. #301830) were added for 45 min before fixation and red blood cell lysis was performed using BD Phosflow Lyse/Fix buffer (BD Biosciences, San Jose, CA, Cat. #558049). Cells were then permeabilized on ice by addition of BD Perm III buffer (BD Biosciences, San Jose, CA, Cat. #558050) and stored at -80°C until use. Prior to staining, cells were washed with PBS containing 0.1% BSA. Optimized concentrations of BUV395-labeled anti-CD45 (BD Biosciences, San Jose, CA, Cat. #563792) and PE-labeled anti-phospho-STAT1 (pY701; Invitrogen, Carlsbad, CA, Cat. #12-9008-42) were added to the cell suspension and incubated for 2 h. Cells were washed with PBS containing 0.1% BSA and analyzed on a BD LSRFortessa™ X20 flow cytometer (BD Biosciences, San Jose, CA) using BD FACSDiva™ software. Data were analyzed using FlowJo V10 analysis software (Flow Jo LLC, Ashland, OR). The extent of STAT phosphorylation was measured by the mean fluorescence intensity (MFI) of pSTAT1 in CD14+ monocytes. Compound dose-response curves were determined using a four-parameter logistic nonlinear regression model from which half-maximal effective concentrations (EC ₅₀ ) were calculated. GraphPad software (San Diego, CA) was used for all statistical analyses.

[00861] The protein tyrosine phosphatases PTPN2 and PTPN1 are negative regulators of several cellular pathways, including JAK/STAT-mediated cytokine signaling (e.g., IFNγ, IFNα, IL2). Inhibition of PTPN2/N1 is expected to increase STAT phosphorylation by delaying the dephosphorylation of STAT proteins. The effects of compounds on IFNγ signaling were assessed by measuring phosphorylation of the direct target of PTPN2/N1, STAT1, as a proximal translational pharmacodynamic marker in human whole blood. Cells contained in whole blood provide close physiologically relevant tuning and also facilitate assessment of small molecule protein binding characteristics and the amount of free drug available to act on its target. In human whole blood containing the active compounds, a dose-dependent increase in STAT1 phosphorylation was observed following IFNγ stimulation. The compounds of the present disclosure enhance IFNγ-induced STAT1 phosphorylation. Table 4 below summarizes the pSTAT EC ₅₀ values for exemplary compounds of the disclosure.

[00862] The protein tyrosine phosphatases PTPN2 and PTPN1 are negative regulators of several cellular pathways, including JAK/STAT-mediated cytokine signaling (e.g., IFNγ, IFNα, IL2). Inhibition of PTPN2/N1 is expected to increase STAT phosphorylation by delaying the dephosphorylation of STAT proteins. The effects of compounds on IFNγ signaling were assessed by measuring phosphorylation of the direct target of PTPN2/N1, STAT1, as a proximal translational pharmacodynamic marker in human whole blood. Cells contained in whole blood provide close physiologically relevant tuning and also facilitate assessment of small molecule protein binding characteristics and the amount of free drug available to act on its target. In human whole blood containing the active compounds, a dose-dependent increase in STAT1 phosphorylation was observed following IFNγ stimulation. The compounds of the present disclosure enhance IFNγ-induced STAT1 phosphorylation. Table 4 below summarizes the pSTAT EC ₅₀ values for exemplary compounds of the disclosure.

Table 4: Comparison of IC ₅₀ values of selected compounds in the B16F10 growth inhibition assay and EC ₅₀ values on IFNγ-induced STAT1 phosphorylation in human whole blood.

Compound B16F10 Growth inhibitor
IC ₅₀ (µM) Human IFNγ induced by whole blood pSTAT1
EC ₅₀ (µM) Compound V 3.2 W connection 4.1 X connection 4.1 Y connection 5.8 38 Z connection 17.8 >500 118 0.11 0.58 133 0.22 1.6 146 <0.05 0.4 177 0.14 2 199 <0.05 0.83 200 <0.05 2.4 259 1.5 14.2 260 0.18 4.4

Example 231: T-cell function tests

[00863] Pan T cells were isolated from C57BL6 splenocytes using the MACS Pan T Cell Isolation Kit II (Miltenyi Biotec, Auburn, CA) according to the manufacturer's instructions. Isolated T cells (200,000 cells/well in a 96-well flat-bottom plate) were cultured in RPMI 1640 supplemented with 10% FBS, 50 nM 2-mercaptoethanol, 100 U/ml penicillin, and 100 μg/ml streptomycin and incubated with 0.3 μM compound or DMSO in duplicate. After 1 hour, CD3/CD28 Dynabeads mouse T cell activator (ThermoFisher Scientific, Waltham, MA) were added at a 1:5 bead to cell ratio to stimulate T cells for 3 days. T cells with or without compound were incubated in the absence of T cell activator beads to assess whether the compounds stimulated T cells non-specifically. After 3 days of stimulation, supernatants were collected and IFNγ and TNFα in the supernatants were assessed using the MSD V-plex assay (Meso Scale Discovery, Rockville, MD).

[00864] Increasing T cell activation and, most importantly, T cell function is a key strategy in new approaches in immune oncology aimed at enhancing tumor immunity. In vitro assays using primary T cells are commonly used to assess the effects of a compound on T cell activation and function.

[00865] An indicator of T cell function important for tumor immunity is the production of proinflammatory, antitumor cytokines such as IFNγ and TNFα. This can be assessed by detecting cytokines in the supernatants of T cells stimulated in vitro. An immunostimulatory compound would be expected to increase the production of IFNγ and TNFα. The compounds of the present invention promote the production of IFNγ and TNFα by stimulated T cells. Importantly, the compounds did not non-specifically increase IFNγ and TNFα production in the absence of TCR stimulation. Table 5 below summarizes the amount of IFNγ and TNFα produced by T cells either stimulated via the TCR (anti-CD3/CD28) or left unstimulated (no stimulation) for 3 days for representative compounds of the description.

Y connection

Table 5: Cytokine data from T cell function assays

Connection No. IFNγ [pg/ml] TNFα [pg/ml] no stimulation anti-CD3/CD28 no stimulation anti-CD3/CD28 DMSO 1,1 49 1,1 73.7 118 1.8 261.3 1,1 159.1 133 1.0 204.1 0.8 142.0 148 1.0 168.4 0.8 123.4 177 1.0 168.2 0.7 113.7 199 1.8 212.9 1,1 147.8 204 1.8 148.8 1,1 105.4 254 0.7 97.0 1,1 91.2 260 0.8 139.6 1,1 100,0 291 0.7 83.3 1,1 91.2 307 1,2 66.7 1,1 89.5 Y connection 1,2 67.2 1.0 32.5

Example 232. Efficiency in vivo PTPN2 inhibitors in the MC38 mouse tumor model and effects on pharmacodynamic markers

Mice

[00866] All experiments were conducted in accordance with the AbbVie Institutional Animal Care and Use Committee and the National Institutes of Health Guide for the Care and Use of Laboratory Animals in an Association for Assessment and Accreditation of Laboratory Animal Care-accredited facility. Female C57Bl/6 mice were obtained from Charles River (Wilmington, MA). Mice were housed in groups of 10 per cage. Food and water were available ad libitum. Animals were acclimated to the animal facilities for at least one week prior to experimentation. Animals were tested on a 12-hour light:12-hour dark cycle (lights on at 0600 hours).

Inoculation and treatment of tumor cells

[00867] Cells were grown in vitro until transfer 3. A total of 1× ¹⁰⁵ viable MC-38 cells were inoculated subcutaneously into the right flank of female C57Bl/6 mice (7-12 weeks old) on Day 0. The injection volume was 0.1 ml and consisted of a 1:1 mixture of S-MEM and Matrigel® (Corning, NY, USA). Tumors were size matched on Day 14 and mice had an average body weight of ~21 g. The average tumor volume (TV) at size matching was approximately 196±64 ^mm3 . Following size matching, treatment was initiated on the same day. Mice were orally dosed twice daily (BID) at 7 and 17 h on Day 21. Mice were dosed (10 mg/kg/dose) with either Compound 118 or vehicle control (n=15 mice/group). Compound 118 was formulated in 10% ethanol, 30% PEG-400, and 60% Phosal-50PG and dosed at 10 ml/kg. Tumor volume was calculated three times per week. Tumor length (L) and width (W) measurements were taken with an electronic caliper and the volume was calculated according to the following equation: V=L x ^W2 /2 using Study Director version 3.1.399.22 (Studylog Systems, Inc, California, USA). Mice were sacrificed when tumor volume was ≤ 3000 ^mm3 or skin ulcers occurred. Tumor growth inhibition (TGI) was calculated as TGI=1-(Mean TV _{Time Point (Treatment)} /Mean TV _{Time Point (Vehicle)} ) for each time point at which tumor volumes were measured. The reported TGI _Max is the highest TGI value for any time point at which tumor volumes were collected for that treatment group.

Flow cytometric analysis of pSTAT5 in mouse whole blood

[00868] Whole blood was collected into EDTA-coated tubes by cardiac puncture from mice on day 8 of compound 118 administration (2 hours after the 16th dose). 90 μL of whole blood was stimulated with 10 μL of mouse IL-2 to achieve a final concentration of 100 ng IL-2/mL (R&D Systems, Minneapolis, MN, Cat. #402-ML) for 20 min at 37°C in 5% _CO2 . Following stimulation, 1.8 mL of pre-warmed BD Phosflow Lysis/Fixation Buffer (BD Biosciences, San Jose, CA) was added for 20 min at 37°C. Cells were washed twice with FACS buffer (Dulbecco's PBS with 0.2% BSA) and incubated for 30 min on ice in cold Perm buffer III (BD Biosciences, San Jose, CA). Cells were washed with FACS buffer and resuspended in 50 μl of FACS buffer with antibodies and stained for 3 h at room temperature with gentle shaking. Antibodies added were a combination of the following: anti-CD3-AF647, clone 145-2C11 (Biolegend, Cat. #564279); anti-CD4-FITC, clone GK1.5 (Biolegend, San Diego, CA, Cat. #100406); anti-pSTAT5 (pY694)-PE, clone 47 (BD Biosciences, San Jose, CA, Cat. #562077); anti-CD45-BUV395, clone 30-F11 (BD Biosciences, San Jose, CA, Cat. #564279). After staining, cells were washed twice with FACS buffer and samples were collected on BD LSRFortessa™ X20 flow cytometers (BD Biosciences, San Jose, CA) and analyzed with FLowJo V10 software (FlowJo, Ashland, OR). The mean fluorescence intensity (MFI) of pSTAT5 was reported as a measure of the amount of phosphorylated STAT5 in the CD3+ T cell population from vehicle- or Compound 118-treated animals.

Granzyme B Staining of CD8 T Cells Flow Cytometry Analysis in Mouse Spleen

[00869] Mice were sacrificed on day 8 of Compound 118 administration (2 hours after the 16th dose) and the spleens were excised. The spleens were dissociated using a MACS soft dissociator (Miltenyi Biotec, Bergisch Gladbach, Germany), red blood cells were lysed, and single cell suspensions were prepared. Splenocytes were stained with the Zombie UV™ Fixable Viability kit (Biolegend, San Diego, CA) diluted in Dulbecco's PBS for 10 min at room temperature to exclude dead cells, followed by staining for surface markers for 45 min on ice using the following flow cytometry antibodies diluted in autoMACS running buffer (Miltenyi Biotec, Bergisch Gladbach, Germany): Brilliant Violet 510-labeled anti-CD45, Brilliant Ultraviolet 395-labeled anti-CD3, Brilliant Violet 786-labeled anti-CD4, APC/Cy7-labeled anti-CD8. Cells were washed twice with autoMACS running buffer, permeabilized with fixation/permeabilization buffer (FoxP3/transcription factor staining buffer kit; eBioscience), and intracellularly stained with PE-labeled granzyme B antibodies diluted in permeabilization buffer (FoxP3/transcription factor staining buffer kit; eBioscience, San Diego, CA) for 1 h on ice. After staining, cells were washed twice with autoMACS running buffer, samples were collected on BD LSRFortessa™ X20 flow cytometers (BD Biosciences, San Jose, CA) and analyzed with FLowJo V10 software (FlowJo, Ashland, OR). The frequency of granzyme B+ cells in the CD8+ T cell population was reported in vehicle- or Compound 118-treated animals.

Measurement of cytokines in mouse plasma

[00870] Whole blood was collected into EDTA-coated tubes by cardiac puncture of mice on day 8 of Compound 118 administration (2 hours after the 16th dose), and plasma was obtained by centrifugation. Plasma cytokines were measured using the Th1/Th2 Cytokine & Chemokine 20-Plex Mouse ProcartaPlex™ Panel 1 (Invitrogen, Carlsbad, CA). IP10 levels (pg/mL) were reported in animals treated with vehicle or Compound 118.

Results

[00871] Tumor cell expression of the phosphatases PTPN2 and its highly homologous analog PTPN1 have recently been described as negative regulators of tumor immune responses. The functional activity of PTPN2 in suppressing extrinsic factor signaling cascades within tumor cells, in particular dephosphorylation of STAT molecules downstream of the IFNγ receptor, has been identified as a significant contributor to the ability of tumor cells to evade or suppress antitumor immune responses. To confirm these claims, specific PTPN2/N1 inhibitors were generated and tested for their ability to inhibit tumor growth and induce antitumor inflammation in a syngeneic mouse tumor model in vivo. Mice were inoculated with the posterior flank of MC-38 mouse colon adenocarcinoma. After two weeks of tumor cell growth, mice began oral BID treatment with either vehicle or Compound 118 for 21 days. Compound 118 was well tolerated with no apparent adverse health effects. However, within 7-10 days of treatment, animals treated with Compound 118 showed apparent tumor stagnation and reduction in tumor size. Ultimately, 70% of Compound 118-treated mice achieved complete cure and the overall TGI _Max was 94% (Table 6). The significant tumor efficacy observed with Compound 118 prompted further studies of the compounds’ direct on-target effects in vivo as well as their effects on anti-tumor immune responses.

[00872] IL2 signaling in T cells promotes T cell homeostasis and proliferation. STAT5 is a signaling molecule in the IL2 pathway and a direct target of PTPN2 and PTPN1, which serve as negative regulators of IL2 signaling. A PTPN2/N1 inhibitor is expected to increase STAT5 phosphorylation upon IL2 stimulation. To demonstrate in vivo target engagement, we measured pSTAT5 levels in T cells from whole blood of animals dosed with a PTPN2/N1 inhibitor following ex vivo stimulation of whole blood with IL2. In mice treated with Compound 118, pSTAT5 levels in whole blood T cells were 1.6-fold higher (MFI=1261±97) than in animals treated with vehicle control (MFI=802±52) (Table 6).

[00873] One of the desirable effects of immunotherapy is the induction of functional cytotoxic T cells, which can improve tumor immunity. In mice treated with Compound 118, the frequency of functional granzyme B (GzB)-producing cells in the cytotoxic CD8+T population in the spleen was 3.9-fold higher (4.3±0.9%) than in animals treated with vehicle control (1.1±0.1%) (Table 6).

[00874] Since a PTPN2/N1 inhibitor promotes IFNγ signaling by increasing the phosphorylation of JAK and STAT signaling molecules, and IP10 is an IFNγ-induced protein, a PTPN2/N1 inhibitor is expected to increase IP10 production. IP10 levels in the plasma of Compound 118-treated mice were 1.7-fold higher (256±30 pg/mL) than in vehicle control-treated animals (153±15 pg/mL) (Table 6).

Table 6: Effect of oral dosing of BID with indicated treatment on tumor growth and PD marker movement in the syngeneic MC-38 tumor model. TGI _Max was determined throughout the study. PD markers were assessed on day 8 of dosing (2 hours after the 16th dose). Data are presented as mean ± SEM.

Compound Tumor growth inhibition (max) vs. vehicle [%] % GzB+ cells in splenic CD8+ T cells pSTAT5 level [MFI] in CD3+ T cells from whole blood stimulated with IL2 IP10 in plasma [pg/ml] Carrier - 1.1±0.1 802±52 153±15 118 94 4.3±0.9 1261±97 256±30

Equivalents and scope of application

[00875] In the claims, the singular forms "a" or "an" may mean one or more unless otherwise stated or otherwise obvious from the context. Claims or descriptions that include "or" between one or more members of a group are satisfactory if one, more, or all of the members of the group are present, used, or otherwise related to the product or process, unless otherwise stated or otherwise obvious from the context. The invention includes embodiments in which exactly one member of the group is present, used, or otherwise related to the product or process. The invention includes embodiments in which more than one or all of the members of the group are present, used, or otherwise related to the product or process.

[00876] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more recited claims are introduced into another claim. For example, any claim that depends on another claim may be amended to include one or more limitations found in any other claim that depends on the same base claim. Where elements are presented in list form, such as in Markush group format, each subgroup of elements is also disclosed, and any element(s) may be deleted from the group. It should be understood that, in general, when the invention or aspects of the invention are referred to as comprising certain elements and/or features, certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and/or features. For simplicity, these embodiments have not been specifically recited herein in the same terms. It should also be noted that the terms "comprising" and "including" are intended to disclose and allow for the inclusion of additional elements or steps. Where ranges are specified, the endpoints are included. Furthermore, unless otherwise stated or otherwise obvious from the context and the understanding of one of ordinary skill in the art, values expressed as ranges may take any specific value or subrange within the stated ranges in various embodiments of the invention, down to tenths of units of the lower limit of the range, unless the context clearly dictates otherwise.

[00877] This application includes various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the present description, the description shall control. In addition, any specific embodiment of the present invention that is known in the art may be expressly excluded from any one or more claims. To the extent that such embodiments are believed to be known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any specific embodiment of the invention may be excluded from any claim for any reason, regardless of whether it is related to the existence of prior art.

[00878] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited by the above description, but rather is set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications can be made to this description without departing from the spirit or scope of the present invention as defined in the following claims.

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LIST OF SEQUENCES

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<120> PROTEIN TYROSINE PHOSPHATASE INHIBITORS AND METHODS OF THEIR

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Lys Phe Arg Met Gly Leu Ile Gln Thr Ala Asp Gln Leu Arg Phe Ser

275 280 285

Tyr Leu Ala Val Ile Glu Gly Ala Lys Phe Ile Met Gly Asp Ser Ser

290 295 300

Val Gln Asp Gln Trp Lys Glu Leu Ser His Glu Asp Leu Glu Pro Pro

305 310 315 320

Pro Glu His Ile Pro Pro Pro Pro Arg Pro Pro Lys Arg Ile Leu Glu

325 330 335

Pro His Asn

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Claims (4)

1. The compound represented by: 2. A compound wherein the compound is 5-{( 7R )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2, wherein the compound is a pharmaceutically acceptable salt of 5-{( 7R )-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidine-1,1,3-trione.