RU2799446C2 - Protein-tyrosinphosphatase inhibitors and methods of their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: herein the compounds, compositions, and methods useful for inhibiting a protein tyrosine phosphatase, such as a non-receptor type 2 protein tyrosine phosphatase (PTPN2) and/or a non-receptor type 2 protein tyrosine phosphatase are provided. The invention relates to a compound which is

and its pharmaceutically acceptable salt.

EFFECT: new compound has been obtained that is suitable for inhibiting protein tyrosine phosphatase, for example, non-receptor type 2 protein tyrosine phosphatase (PTPN2) and/or non-receptor type 1 protein tyrosine phosphatase (PTPN1), and for the treatment of associated diseases, disorders and conditions that respond favorably to for treatment with PTPN1 or PTPN2 inhibitors, such as cancer or metabolic disorders.

4 cl, 227 ex, 6 tbl

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority over U.S. Provisional Application No. 62/688226, filed June 21, 2018, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Cancer immunotherapy regimens targeting mechanisms to evade immune surveillance, including checkpoint blockade (eg, PD-1/PD-L1 and CTLA-4 blocking antibodies), have been shown to be effective in treating a variety of cancers, significantly improving outcome in some populations populations refractory to conventional treatments. However, incomplete clinical responses and the development of intrinsic or acquired resistance will continue to limit patient populations that can benefit from checkpoint blockade.

Non-receptor protein tyrosine phosphatase type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the subfamily of class 1 phosphotyrosine-specific phosphatases that control multiple cellular regulatory processes by removing phosphate. groups of tyrosine substrates. PTPN2 is ubiquitously expressed, but its 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 splicing variants: a 45 kD form that contains a nuclear localization signal at the C-terminus upstream of the splice junction, and a canonical 48 kD 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 cellular stress conditions. Both isoforms share the N-terminal phosphotyrosine phosphatase catalytic domain. PTPN2 downregulates signaling of non-receptor tyrosine kinases (eg, JAK1, JAK3), receptor tyrosine kinases (eg, INSR, EGFR, CSF1R, PDGFR), transcription factors (eg, STAT1, STAT3, STAT5a/b), and Src family kinases (eg, Fyn , Lck). As a critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also referred to as PTP1B) and has similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003).

In vivo loss-of-function genetic screening data using CRISPR/Cas9 genome editing in the B16F10 mouse transplantable tumor model shows that deletion of the Ptpn2 gene in tumor cells improved response to the GM-CSF-secreting vaccine (GVAX) immunotherapy regimen plus blocking the PD checkpoint - 1 (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 showed that genes known to be involved in immune surveillance evasion, including PD-L1 and CD47, are also depleted under the pressure of selective immunotherapy, while genes involved in the IFNγ signaling pathway including IFNGR, JAK1 and STAT1 are enriched. These observations point to the proposed role of therapeutic strategies that improve IFNγ uptake and signaling in enhancing the efficacy of cancer immunotherapy regimens.

Non-receptor protein tyrosine phosphatase 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 suppressing both insulin and the leptin receptor signaling pathway (Kenner KA et al., J Biol Chem 271: 19810-19816, 1996). Animals deficient in PTP1B have improved glucose regulation and lipid profile and are resistant to weight gain when treated with a high fat diet (Elchebly M. et al., Science 283: 1544-1548, 1999). Thus, PTP1B inhibitors are expected to be useful in the treatment of type 2 diabetes, obesity and metabolic syndrome.

SUMMARY OF THE INVENTION

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

For example, this document describes a compound represented by formula (I):

(I);

(I);

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N -oxide, stereoisomer or isotopically enriched variant thereof, wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, -N(R ^a )-C _1-6 alkyl and -C _1-6 alkylene -5-6 membered heterocyclyl;

where C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, -N(R ^a )-C _1-6 alkyl and -C _1-6 alkylene-5-6 membered heterocyclyl may optionally be substituted at one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and moreover, if -C _1-6 alkylene-5-6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

R ² is selected from the group consisting of hydrogen, hydroxyl, -CHF ₂ , -CH ₂ OH, -CH ₂ CN, -CH ₂ -OC _1-6 alkyl, -CH ₂ -N(R ^a )-C _1-6 alkyl, C _2-6 alkyl, C _2-6 alkenyl, -OC _1-6 alkyl, -N(R ^a )-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 , -N(R ^a )-C(O)-OC _1-6 alkyl, -C _3-6 cycloalkyl, -OC _3-6 cycloalkyl, C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkenylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -OC _1-6 alkylene-5-6 membered heteroaryl, -O-4 -6 membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene-4-6 membered heterocyclyl and -OC _1-6 alkylene-4-6 membered heterocyclyl;

where -CH ₂ -OC _1-6 alkyl, -CH ₂ -N(R ^a )-C _1-6 alkyl, C _2-6 alkyl, C _2-6 alkenyl, -OC _1-6 alkyl, -N(R ^a )-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, -N(R ^a )-C(O)-OC _1-6 alkyl, -C _3-6 cycloalkyl , -OC _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkenylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6 membered heteroaryl, -OC _1-6 alkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, -O-4-6 membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene -4-6 membered heterocyclyl and -OC _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 moreover, if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene-4-6 membered heterocyclyl or -OC _1-6 alkylene-4 -6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

or R ¹ and R ² taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted with one or more substituents each independently selected from the group consisting of halo, hydroxyl, cyano, C _1-6 alkyl and C _1-6 alkoxy; where C _1-6 alkyl and C _1-6 alkoxy may optionally be substituted with one, two, three or more substituents each independently selected from R ^P ;

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

where -C _1-6 alkyl, -OC _1-6 alkyl, -N(R ^a )-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 and -C _1-6 alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbon atoms one, two, three or more substituents each independently selected from R ^g ; and where -C _1-6 alkylene _-4-6 membered heterocyclyl contains a substituted ring nitrogen atom, this 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; where 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 moreover, if -C _1-6 alkylene-4-6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

where at least one of R ¹ , R ² , R ³ and R ⁴ is not hydrogen;

R ⁵ 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; where 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 moreover, if -C _1-6 alkylene-4-6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

R ⁶ is hydrogen;

R ⁷ is hydrogen;

for each occurrence, R ^g is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, 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, phenyl, C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -(CO)-(NR ^a )-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 )-, 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 )-, 4-6 membered heterocyclyl-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-, -P(O)(C _1-3 alkyl) ₂ 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, phenyl, C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene- _{C 3-6} cycloalkyl, -(CO)-(NR ^a )-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 )-, 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 )-, 4-6 membered heterocyclyl-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-, -P(O)(C _1-3 alkyl) ₂ and C _1-6 alkoxy-C _1-6 alkyl- may optionally be substituted with one, two , three or more substituents each independently selected from R ^P ;

for each occurrence, R ^h is independently selected 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-C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, 4-6 membered heterocyclyl-S(O) ₂ -, 4-6 membered heterocyclyl-C _1-6 alkyl- S(O) ₂ -, 5-6 membered heteroaryl-S(O) ₂ -, phenyl-S(O) ₂ -, phenyl-C _1-6 alkyl-S(O) ₂ -, C _1-6 alkyl- C(O)-, C _1-6 cycloalkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)-, R ^a R ^b N-SO ₂ - and -P(O)(C _1-3 alkyl) ₂ ; where C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkyl-C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ - , C _3-6 cycloalkyl-S(O) ₂ -, 4-6 membered heterocyclyl-S(O) ₂ -, 4-6 membered heterocyclyl-C _1-6 alkyl-S(O) ₂ -, 5-6 membered heteroaryl-S(O) ₂ -, phenyl-S(O) ₂ -, phenyl-C _1-6 alkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 cycloalkyl -C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)-, R ^a R ^b N-SO ₂ - and -P(O) (C _1-3 alkyl ) ₂ may optionally be substituted with one, two, three or more substituents each independently selected from R ^P ;

for each occurrence, R ^p is independently selected from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, 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 )-;

for each occurrence, R ^a and R ^b are independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl; where C _1-6 alkyl may optionally be substituted with one or more substituents, each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and C _1-6 alkoxy (optionally substituted with one, two or three fluorine atoms);

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

w is 0, 1, or 2.

This document also describes the compound represented by formula (II):

(II)

(II)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N -oxide or stereoisomer thereof, wherein:

X is selected from the group consisting of -O- and -N(R ^a )-;

L is straight or branched C _1-6 alkylene;

R ^2-II is selected from the group consisting of hydrogen, cyano, -NR ^a R ^b , C _1-2 alkoxy, C _3-6 cycloalkyl-SO ₂ -N(R ^a )-, C _1-6 alkyl-SO ₂ -N(R ^a )-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C _3-6 cycloalkyl; wherein phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NR ^a R ^b , C _1-2 alkyl (optionally substituted with one, two or three halogens) and C _1-2 alkoxy (optionally substituted with one, two or three halogens); and wherein, if the 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted with C _1-3 alkyl;

R ⁵ is selected from the group consisting of hydrogen, deuterium and halogen;

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

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

for each case each

R ^a and R ^b are independently selected from the group consisting of hydrogen and C _1-3 alkyl.

This document also describes the compound represented by formula (III):

(III);

(III);

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N -oxide or stereoisomer thereof, wherein:

X ^III is selected from the group consisting of a bond, -CH ₂ -, -NR ^a -, -O-, -O-CH ₂ - and -OCH ₂ -CH ₂ -

m is 1, 2 or 3;

n is 1, 2 or 3;

R ^1-III is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR ^a R ^b , C _1-2 alkyl (optionally substituted with one, two or three halogens) and C _1-2 alkoxy (optionally substituted with one, two or three halogens);

R ^2-III is selected from the group consisting of hydrogen, C _1-4 alkyl, -C(O)-C _1-4 alkyl, -C(O)-OC _1-4 alkyl, -C(O)-N( R ^a )-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -C _3-6 cycloalkyl; where C _1-4 alkyl, -C(O)-C _1-4 alkyl, -C(O)-OC _1-4 alkyl, -C(O)-N(R ^a )-C _1-4 alkyl, - S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -C _3-6 cycloalkyl may optionally be substituted with one, two or three substituents, each independently selected from the group consisting of halogen, hydroxyl, cyano, - NR ^a R ^b , C _1-2 alkyl (optionally substituted with one, two or three halogens) and C _1-2 alkoxy (optionally substituted with one, two or three halogens);

R ⁵ is selected from the group consisting of hydrogen, deuterium and halogen;

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

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

for each occurrence, each R ^a and R ^b is independently selected from the group consisting of hydrogen and C _1-3 alkyl.

The compound further disclosed herein is selected from the group consisting of:

5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione; 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl propan-2-ylcarbamate;

5-(9-fluoro-7-hydroxynaphtho[2,1- b ]furan-8-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-methoxy( ^4-2 H)naphthalen-2-yl]( ^4,4-2 H ₂ )-1λ ^6,2,5 -thiadiazolidin-1,1,3 -trione;

5-[1-fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione; 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile;

5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile ;

5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[( ² H ₃ )methyloxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile ;

5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione;

5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)( ^4,4-2 H ₂ )-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide ;

5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile;

[1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl] acetonitrile;

5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropylmethyl)-1 H -pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{1-fluoro-3-hydroxy-7-[( 1H- pyrazol-4-yl)methoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-[1-fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione;

5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3 S )-3-hydroxybutoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3 R )-3-hydroxybutoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4 R )-4-hydroxypentyl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4 R )-4-hydroxypentyl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4 S )-4-hydroxypentyl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-{1-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

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

1-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropane -1-carbonitrile;

5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

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

5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}butanenitrile;

5-[1-fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-{1-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}methyl)cyclopropan-1 -carbonitrile;

5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[3-(1 H -pyrazol-1-yl)propoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-(7-{1-[(4-Aminophenyl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(1 H -pyrazol-1-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(piperidin-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-(7-{1-[(2-Aminophenyl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropan-1 -carbonitrile;

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

5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetonitrile;

5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

(2 E )-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]prop-2- ennitrile;

5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2- tert -Butoxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[ rac -(1 R ,2 R )-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1, 3-trione;

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

5-{7-[3-(2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(4-methyl-1 H -imidazol-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-[7-(azetidin-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetonitrile;

5-[1-fluoro-3-hydroxy-7-(methoxymethyl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione;

5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3 S )-pyrrolidin-3-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3 R )-pyrrolidin-3-yl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(8-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-(4-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[( E )-2-cyclopropylethenyl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(1 E )-4-methylpent-1-en-1-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ^6,2,5- thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(1 E )-3-methoxyprop-1-en-1-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(1,1-dioxo-1λ ⁶ -thian-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{2-[methyl(2-methylpropyl)amino]ethoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-{1-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-(7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-[1-fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-{1-fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(3,6-dihydro-2 H -pyran-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[7-(2,5-dihydro-1 H -pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[1-fluoro-3-hydroxy-7-(pyridin-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(azetidin-3-yl)methyl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

N -(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] amino}acetamide;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} -N -methylbutanamide;

N -ethyl- N '-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] hydroxy}ethyl)urea;

5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(1-chloro-3-hydroxypropan-2-yl)oxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{1-fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalene-2-yl}-1λ ⁶ , 2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3,7-dihydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-propoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

{[8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetic acid;

N -(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] hydroxy}acetamide;

N, N -diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} acetamide;

5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione;

5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{1-fluoro-3-hydroxy-7-[1-(oxolane-3-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2.5 -thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropan-1-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl }-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropan-1-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl }-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{1-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}naphthalene-2-yl)-1λ ^6,2,5 -thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(4,4,4-trifluorobutan-1-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl }-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(butan-1-sulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione;

5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl )-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]-2,5-dihydro -1 H -pyrrole-1-sulfonyl}pentanenitrile;

5-{1-fluoro-3-hydroxy-7-[1-(pentan-2-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione;

N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)oxetane -3-sulfonamide;

5-[1-fluoro-3-hydroxy-7-(piperidin-4-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(2-methylpropan-1-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-ethoxy-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)-1 H -pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-(1-fluoro-3-hydroxy-7-{[(3 R )-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione;

5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(1,3-dimethyl- 1H -pyrazole-4-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2 -yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)ethanesulfonamide ;

5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]-3-hydroxynaphthalene-2-yl}-1λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutan-1-sulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(thiophene-3-sulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

methyl (2 S )-2-amino-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2- yl]hydroxy}butanoate;

5-{7-[(3,5-dimethyl-1 H -pyrazol-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-[7-(3,5-dimethyl-1 H -pyrazol-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-1 H -imidazole-4-carbonitrile ;

and a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N -oxide or stereoisomer thereof.

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is formulated as a pharmaceutically acceptable composition comprising the described compound and a pharmaceutically acceptable carrier.

This document also describes a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound described herein, for example, a compound of formula (I), formula (II), or formula (III) in combination with an additional therapeutic agent . In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, an immunotherapeutic agent selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

For example, this document describes a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound described herein, for example, a compound of formula (I), formula (II), or formula (III).

Additionally, this 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, for example, a compound of formula (I), formula (II), or formula (III).

Provided herein, for example, is 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 described herein, e.g., a compound of formula (I), formula (II), or formula (III) .

For example, this document describes a method of suppressing further weight gain in an overweight or obese patient in need thereof, comprising administering to the patient an effective amount of a compound described herein, for example, a compound of formula (I), formula (II), or formula ( III).

Additionally, this document describes a method of treating a metabolic disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound described herein, for example, a compound of formula (I), formula (II), or formula (III).

In some embodiments of the invention, the method includes the treatment of cancer. In some embodiments, the cancer includes pancreatic cancer, brain cancer, multiple myeloma, melanoma, or secretory cell cancer. In some embodiments, the method includes treating a metabolic disease. In some embodiments, the metabolic disease includes non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Sayre disease.

Also described herein is a composition for use in the treatment of cancer in a patient in need thereof, the composition comprising a compound as described herein, for example a compound of formula (I), formula (II), or formula (III), in combination with additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, an immunotherapeutic agent selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

For example, this document describes a composition for use in the treatment of cancer in a patient in need thereof, and this composition includes a compound described in this document, for example, a compound of formula (I), formula (II) or formula (III).

Additionally, this document describes a composition for use in the treatment of type 2 diabetes in a patient in need thereof, and this composition includes a compound described in this document, for example, a compound of formula (I), formula (II) or formula (III).

Provided herein, for example, is a composition for use in the treatment and/or control of obesity in a patient in need thereof, the composition comprising a compound as described herein, for example a compound of formula (I), formula (II), or formula (III).

For example, this document describes a composition for use in suppressing further weight gain in an overweight or obese patient in need of it, and this composition includes a compound described in this document, for example, a compound of formula (I), formula (II) or formula (III).

Additionally, this document describes a composition for use in the treatment of a metabolic disorder in a patient in need thereof, and this composition includes a compound described in this document, for example, a compound of formula (I), formula (II) or formula (III).

In some embodiments, the cancer includes pancreatic cancer, brain cancer, multiple myeloma, melanoma, or secretory cell cancer. In some embodiments, the metabolic disease includes non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Sayre disease.

SUMMARY OF THE SEQUENCE LISTING

Incorporated herein by reference in its entirety, the Sequence Listing, entitled "CLS-014WO_SEQ_ID_List_ST25", comprising SEQ ID NO: 1 to SEQ ID NO: 3, which includes the amino acid sequences described herein. The sequence listing was provided in ASCII text format via EFS. The sequence listing was first created on June 13, 2019 and is 8 KB in size.

DETAILED DESCRIPTION OF THE INVENTION

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

Definitions

Chemical definitions

Specific functional group definitions 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.75^th Ed., inside the cover, and specific functional groups are usually defined as described in it. In addition, the 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 Advanced Organic Chemistry, 5th ed., 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 ed., Cambridge University Press, Cambridge, 1987.

The abbreviations used herein have a generally accepted meaning in the chemical and biological state of the art. The chemical structures and formulas set forth herein are constructed in accordance with standard chemical valency rules known in the chemical arts.

The compounds described herein may contain one or more asymmetric centers and thus may exist in a variety of isomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of an individual 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. Isomers can be isolated from 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 the preferred isomers can be obtained by asymmetric synthesis. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al. , Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This description further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

In the context of this document, a pure enantiomeric compound essentially does not contain other enantiomers or stereoisomers of this compound (ie, is in an enantiomeric excess). In other words, the "S" form of the compound is essentially free of the "R" form of the compound and thus is in an enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than 75 wt.%, more than 80 wt.%, more than 85 wt.%, more than 90 wt.%, more than 91 wt.%, more than 92 wt.%, more than 93 wt.%, more than 94 wt.%, more than 95 wt.%, more than 96 wt.%, more than 97 wt.%, more than 98 wt.%, more than 99 wt.%, more than 99.5 wt.%, or more than 99.9 wt.% of the enantiomer. In some embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, the enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound may contain, for example, about 90% of an excipient and about 10% of an enantiomerically pure R compound. In some embodiments, an enantiomerically pure R-compound in such compositions may contain, for example, at least about 95% wt. R-compounds and not more than 5% wt. S-connections from the total mass of the connection. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% of an excipient and about 10% of an enantiomerically pure S compound. In some embodiments, the enantiomerically pure S-compound in such compositions may contain, for example, at least about 95% wt. S-connections and not more than about 5% wt. R-compounds from the total mass of the compound. In some embodiments, the active ingredient may be formulated with little or no excipient or carrier.

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

The articles "a" and "an" can be used here to refer to one or more than one ( i.e. at least one) of the grammatical objects of the article. By way of example, "analogue" means one analogue or more than one analogue.

When a range of values is specified, it must cover every value and subrange within the range. For example, "C ₁ -C ₆ alkyl" is intended to cover C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C 1 -C 6 , C _{1 -C 5 ,} C _{1 -C 4} , C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ - C ₄ , C ₄ -C ₆ , C ₄ -C ₅ and C ₅ -C ₆ alkyl.

The following terms are intended to have the meanings given below and are useful in understanding the description and intended scope of the present invention.

"Alkyl" refers to the radical of a straight or branched saturated hydrocarbon group that has from 1 to 20 carbon atoms ("C ₁ -C ₂₀ alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C ₁ -C ₁₂ alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C ₁ -C ₈ alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C ₁ -C ₆ alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C ₁ -C ₅ alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C ₁ -C ₄ alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C ₁ -C ₃ alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C ₁ -C ₂ alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C ₁ alkyl"). In some embodiments, the alkyl group has 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 ), t-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 ). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ) and the like. Each example of an alkyl group may be independently optionally substituted, that is, unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In a specific embodiment of the invention, the alkyl group is an unsubstituted C _1-10 alkyl (eg, -CH ₃ ). In a specific embodiment of the invention, the alkyl group is an unsubstituted C _1-6 alkyl. Common alkyl abbreviations 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 ).

The term "alkylene", by itself or as part of another substituent, means, unless otherwise indicated, a divalent radical derived from alkyl, by way of example, but not limited to, such as -CH ₂ CH ₂ CH ₂ CH ₂ -. Typically, an alkyl (or alkenyl) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. 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 as, for example, a C ₁ -C ₆ membered alkylene, where the term "membered" refers to non-hydrogen atoms within the moiety.

"Alkenyl" refers to a straight or branched hydrocarbon group radical that has 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C ₂ -C ₂₀ alkenyl"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C ₂ -C ₁₀ alkyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C ₂ -C ₈ alkyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C ₂ -C ₆ alkyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C ₂ -C ₅ alkyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C ₂ -C ₄ alkyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C ₂ -C ₃ alkyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C ₂ alkenyl"). The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or external (such as 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 C ₂ -C ₆ alkenyl groups include the aforementioned C _2-4 alkenyl groups, as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ) and the like. Additional examples of alkenyls include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ) and the like. Each example of an alkenyl group may be independently optionally substituted, eg unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In particular embodiments, the alkenyl group is an unsubstituted C _2-10 alkenyl. In particular embodiments, the alkenyl group is an unsubstituted C _2-6 alkenyl.

"Aryl" refers to a radical monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., which has 6, 10, or 14 π electrons shared in the ring system) having 6-14 ring carbon atoms and zero heteroatoms, included in the aromatic ring system ("C ₆ -C ₁₄ aryl"). In some embodiments, the aryl group has six ring carbons ("C ₆ aryl"; eg, phenyl). In some embodiments, the aryl group has ten ring carbons ("C ₁₀ aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbons ("C ₁₄ aryl"; eg, anthracyl). An aryl group can be described as, for example, C ₆ -C ₁₀ membered aryl, where the term "membered" refers to non-hydrogen atoms of the ring within the moiety. The aryl group includes, but is not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example of an aryl group may be independently optionally substituted, ie unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents. In specific embodiments of the invention, the aryl group is an unsubstituted C ₆ -C ₁₄ aryl. In specific embodiments of the invention, the aryl group is a substituted C ₆ -C ₁₄ aryl.

In specific embodiments, the aryl group is substituted with one or more groups selected from halogen, C ₁ -C ₈ alkyl, halo-C ₁ -C ₈ alkyl, halooxy-C ₁ -C ₈ alkyl, cyano, hydroxy, alkoxy C ₁ -C ₈ alkyl and amino.

Exemplary substituted aryls include the following

where one of R ⁵⁶ and R ⁵⁷ may be hydrogen and at least one of R ⁵⁶ and R ⁵⁷ are each independently selected from C ₁ -C ₈ alkyl, halo-C ₁ -C ₈ alkyl, 4-10 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) O alkyl, C (O) O aryl, 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( O ₂ )-aryl; or R ⁵⁶ and R ⁵⁷ may be combined to form a cyclic ring (saturated or unsaturated) of 5-8 atoms, optionally containing one or more heteroatomic groups selected from the group N, O, S, S(O) or S(O) ₂ .

Other representatives of aryl groups have a fused heterocyclic group, including the following:

where 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 are 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 heterocyclyl.

"Arylene" and "heteroarylene", alone or as part of another substituent, means 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, benzisoxazolyl, imide zopyrimidyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothipzolyl, purinyl, benzimidazolyl, isoquinolinyl, 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 heteroaryl series described above are non-limiting examples of heteroarylene.

"Halogen" independently or as part of another substituent means, unless otherwise indicated, a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom. The term "halide" by itself or as part of another substituent refers to to a fluoride, chloride, bromide or iodide atom. In specific embodiments, the halogen group is either fluorine or chlorine.

Additionally, terms such as "haloalkyl" should include monohaloalkyl and polyhaloalkyl. For example, the term "C ₁ -C ₆ alkyl halide" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

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, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, S and Si can be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Illustrative examples of heteroalkyl groups include, but are not limited to: -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -S(O)-CH ₃ , -S(O) ₂ -CH _3, -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH =CH-O-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ , -CH=CH-N(CH ₃ )-CH ₃ , -O-CH ₃ and -O- CH ₂ -CH ₃ . Up to two or three heteroatoms may be consecutive, for example, for example -CH ₂ -NH-OCH ₃ and -CH ₂ -O-Si(CH ₃ ) ₃ . When "heteroalkyl" is set forth followed by a listing of specific heteroalkyl groups such as -CH ₂ O-CH ₃ , -NR ^{B RC} , or the like, it should be understood that the terms heteroalkyl and -CH ₂ O-CH ₃ or -NR ^B R ^C are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are listed to add clarity. Thus, the term "heteroalkyl" should not be interpreted here as excluding specific heteroalkyl groups such as -CH ₂ O-CH ₃ , -NR ^{B RC} or the like.

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

"Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system ( e.g. having 6 or 10 π electrons shared in the ring system) having ring carbon atoms and 1-4 ring heteroatoms present in the aromatic ring system , where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In a heteroaryl group that contains one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms on one or both rings. "Heteroaryl" also includes ring systems where the heteroaryl ring, as defined above, is fused to one or more aryl groups, where 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 a condensed (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom ( e.g. indolyl, quinolinyl, carbazolyl and the like), the point of attachment can be on any ring, i.e. , either in the ring bearing the heteroatom ( e.g. 2-indolyl), or in a ring that does not contain a heteroatom ( e.g. 5-indolyl). A heteroaryl group may be described as, for example, a 6- to 10-membered heteroaryl, where the term "membered" refers to non-hydrogen atoms within the moiety.

In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system that has ring carbon atoms and 1-4 ring heteroatoms present in an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in an aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system that has ring carbon atoms and 1-4 ring heteroatoms present in an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- 6 membered heteroaryl"). In particular embodiments of the invention, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each example of a heteroaryl group may be independently optionally substituted, ie unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In specific embodiments of the invention, the heteroaryl group is a substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Illustrative examples of 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, thiazinyl and tatrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Illustrative examples of 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthia diazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following formulas:

where 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.

"Cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group containing from 3 to 10 ring carbon atoms ("C ₃ -C ₁₀ cycloalkyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, the cycloalkyl group has 3 to 8 carbon atoms ("C ₃ -C ₈ cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 carbon atoms ("C ₃ -C ₆ cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 carbon atoms ("C ₃ -C ₆ cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 carbon atoms (“C ₅ -C ₁₀ cycloalkyl”). A cycloalkyl group can be described, for example, as a C ₄ -C ₇ membered cycloalkyl, where the term "membered" refers to non-hydrogen ring atoms within the moiety. Illustrative C ₃ -C ₆ cycloalkyl groups include, without limitation, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ) and the like. Exemplary C ₃ -C ₈ cycloalkyl groups include, without limitation, the aforementioned C ₃ -C ₆ cycloalkyl groups, as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cyclosheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl ( C ₈ ), cyclooctenyl (C ₈ ), cubanyl (C ₈ ), bicyclo[1.1.1]pentanyl (C ₅ ), bicyclo[2.2.2]octanyl (C ₈ ), bicyclo[2.1.1]hexanyl (C ₆ ), bicyclo[3.1.1]heptanyl (C ₇ ) and the like. Exemplary C ₃ -C ₁₀ cycloalkyl groups include, without limitation, the aforementioned C ₃ -C ₈ cycloalkyl groups, as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro- 1 H -indenyl (C ₉ ), decahydronaphthalene (C ₁₀ ), spiro[4.5]decanyl (C ₁₀ ) and the like. As follows from the above examples, in specific embodiments of the invention, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl"), or contains 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 where the cycloalkyl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbon atoms still indicates the number of carbon atoms in the cycloalkyl ring system. Each example of a cycloalkyl group may be independently optionally substituted, eg, unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C ₃ -C ₁₀ cycloalkyl. In specific embodiments of the inventions, the cycloalkyl group is a substituted C ₃ -C ₁₀ cycloalkyl.

In some embodiments, "cycloalkyl" is a monocyclic, saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C ₃ -C ₁₀ cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 carbon atoms ("C ₃ -C ₈ cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 carbon atoms ("C ₃ -C ₆ cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 carbon atoms ("C ₅ -C ₆ cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 carbon atoms (“C ₅ -C ₁₀ cycloalkyl”). Examples of C ₅ -C ₆ cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of C ₃ -C ₆ cycloalkyl groups include the aforementioned C ₅ - ₆ cycloalkyl groups, as well as cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C ₃ -C ₈ cycloalkyl groups include the aforementioned C ₃ -C ₆ cycloalkyl groups, as well as cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise indicated, each example of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C ₃ -C ₁₀ cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C ₃ -C ₁₀ cycloalkyl.

"Heterocyclyl" or "heterocyclic" refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and from 1 to 4 ring heteroatomic groups, each heteroatomic group being independently selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g. , S, S(O) and S(O) ₂ ), boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment may be carbon or nitrogen, as valency permits. The heterocyclic group may be either monocyclic ("monocyclic heterocyclic") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") and may be saturated or may be partially unsaturated. Heterocyclic bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems where a heterocyclic ring as defined above is fused to one or more cycloalkyl groups, where the point of attachment is on either the cycloalkyl or heterocyclyl ring, or ring systems where the heterocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups where the point of attachment is on the heterocyclic ring, in which case the number of ring members continues to refer to the number of ring members in the heterocyclic ring system. A heterocyclyl group can be described, for example, as a 3-7 membered heterocyclyl, where the term "membered" refers to non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S(O ) and S(O) ₂ ), boron, phosphorus, and silicon, inside the fragment. Each example of a heterocyclic group may be independently optionally substituted, eg, unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In some embodiments, the heterocyclic group is an unsubstituted 3-10 membered heterocyclyl. In some embodiments of the invention, the heterocyclic group is a substituted 3-10 membered heterocyclyl. In some embodiments of the invention, the heterocyclic group is a substituted 4-6 membered heterocyclyl.

In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S( O) and S(O) ₂ ), boron, phosphorus and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S( O) and S(O) ₂ ) ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S( O) and S(O) ₂ ) ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (eg, S, S(O) and S(O) ₂ ). In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (eg, S, S(O) and S(O) ₂ ). In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (eg, S, S(O) and S(O) ₂ ).

Typical 3-membered heterocyclic groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Illustrative example of 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Illustrative examples of 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidin-2-one. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, without limitation, azepanil, oxepanil, and thiepanil. Exemplary 8-membered heterocyclic groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C ₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

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

where 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 heterocyclic rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amine, aminocarbonyl ( e.g. amido), aminocarbonylamine, 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 and -S(O) ₂ -aryl. Substituent groups include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

"Nitrogen-containing heterocyclyl" group means a 4-7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but not limited to, morpholine, piperidine ( for example , 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 piperazon.

"Amino" refers to the radical -NR ⁷⁰ R ⁷¹ where R ⁷⁰ and R ⁷¹ are each independently 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 .

"Cyano" refers to the -CN radical.

"Hydroxy" or "hydroxyl" refers to the -OH radical.

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

Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl , "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether or not it precedes the term "optionally" means that at least one hydrogen present in the group (e.g., a carbon or nitrogen atom) is replaced by a valid substituent, e.g., a substituent which, when substituted, results in a stable a compound, for example, a compound that does not spontaneously undergo transformation such as rearrangement, cyclization, elimination or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituent is either the same or different at each position. The term "substituted" is intended to include substitution of all acceptable substituents on organic compounds, such as any of the substituents described herein, resulting in a stable compound. The present invention contemplates any and all such combinations in order to obtain a stable connection. For the purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and/or any suitable substituent as described herein that satisfies the valency of the heteroatoms and results in the formation of a stable moiety.

Two or more substituents may optionally be attached to form aryl, heteroaryl, cycloalkyl or heterocyclyl groups. Such so-called ring-forming substituents are usually, although not necessarily, found in the cyclic base structure. In one embodiment of the invention, ring-forming substituents are attached to adjacent elements of the basic structure. For example, two ring-forming substituents attached to adjacent elements of the cyclic base structure create a fused ring structure. In one embodiment of the invention, ring-forming substituents are attached to one member of the basic structure. For example, two ring-forming substituents attached to the same member of the base structure create a fused ring structure. In yet another embodiment of the invention, ring-forming substituents are attached to one member of the basic structure.

A "counterion" or "anionic counterion" is a negatively charged group bonded to a cationic quaternary amino group to maintain electron neutrality. Illustrative counterions include halide ions ( eg F ^- , Cl ^- , Br ^- , I ^- ), NO ₃ ^- , ClO ₄ ^- , OH ^- , H ₂ PO ₄ ^- , HSO ₄ ^- , sulfonate ions ( eg methanesulfonate, trifluoromethanesulfonate , p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate and the like) and carboxylate ions ( e.g. acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate and the like).

By "pharmaceutically acceptable salts" is meant salts of the active compounds which are prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of this invention contain relatively acidic functionalities, 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 sodium, potassium, calcium, ammonium, an organic amino group, or a magnesium salt or the like. When the compounds of this 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 pure 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, monocarboxylic, phosphoric, monohydrogen phosphate, dihydrogen phosphate, sulfuric, hydrogen sulfate, hydroiodic or phosphorous acids and the like, 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-tolylsulfonic, citric, tartaric, methanesulfonic and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Some specific compounds of this invention contain both basic and acidic functional groups which allow the compounds to be converted into base or acid salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present invention. Salts are generally more soluble in aqueous or other protic solvents, which are the respective base forms. In other cases, the preparation may be a lyophilized powder in the first buffer, for example, in 1 mmol-50 mmol histidine, 0.1% -2% sucrose, 2-7% mannitol at a pH of 4.5 to 5.5, which is combined with a second buffer before use.

Thus, the compounds of the present invention may exist as salts such as pharmaceutically acceptable acids. This invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates )-tartrates, (-)-tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

The neutral forms of the compounds are preferably reduced 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 various salt forms in some physical properties, such as solubility in polar solvents.

In addition to salt forms, the present invention relates to compounds that are in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to obtain the compounds of this invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch with a suitable enzyme or chemical.

Some compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of this invention. Certain compounds of this invention may exist in several crystalline or amorphous forms. In general, all physical forms are equivalent for the use contemplated by this invention and are intended to be within the scope of this invention.

In the context of this document, the term "salt" refers to acidic or basic salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable 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.

Certain compounds of the present invention having asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)- or as (D)- or (L)- for amino acids and individual isomers, cover the scope of the present invention. The compounds of the present invention do not include those known in the art to be too unstable for synthesis and/or isolation. This invention is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers can be obtained using chiral synthons or chiral reagents or separated using conventional methods. When the compounds described herein contain olefin bonds or other centers of geometric asymmetry, and unless otherwise indicated, the compounds are intended to include both E and Z geometric isomers.

As used herein, the term "isomers" refers to compounds with the same number and type of atoms, and therefore the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another.

Those skilled in the art will appreciate that certain compounds of this invention may exist in tautomeric forms and all such tautomeric forms of the compounds are part of this invention.

"Treatment" or "treatment" includes preventing or delaying the onset of symptoms, complications, or biochemical signs of a disease, alleviating or ameliorating symptoms, or arresting or inhibiting the further progression of a disease, condition, or disorder. "Cure" or "treatment" includes any effect, such as attenuating, 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 occurrence , growth, metastasis, or progression of cancer, or by reducing a symptom of cancer. The term "treatment" and related terms include preventing an injury, pathology, condition, or disease (eg, preventing the development of one or more of the symptoms of the disease, disorder, or condition described herein).

An "effective amount" is an amount sufficient to achieve the intended purpose (eg, achieve the effect for which it is administered, treat a disease, decrease enzymatic activity, increase enzymatic activity, or reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to assist in the treatment, prevention, or reduction of 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 the amount of the drug that, when administered to a subject, will have 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 occurrence (or recurrence) of an injury, diseases, pathologies or conditions or their symptoms. The full prophylactic effect is not necessarily due to the introduction of a single dose and may occur only after a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amount will depend on the goal of treatment and will be determined by those skilled in the art using known techniques (see, for example, 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).

"Reduction" of a symptom or symptoms (and the grammatical equivalents of this expression) means a decrease in the severity or frequency of the symptom(s) or elimination of the symptom(s).

"Control" or "control experiment" is used according to its usual meaning and refers to an experiment in which the subjects or reagents of the experiment are treated in the same way as in a parallel experiment, except for skipping a procedure, reagent, or changing the experiment. In some cases, the control is used as a standard for comparison when evaluating experimental effects.

"Contact" is used in accordance with its usual meaning and refers to the process of allowing at least two different species (eg, chemical compounds, including biomolecules or cells) to become close enough to respond, interact, or physically contact. Meanwhile, it should be understood that the reaction product can be obtained directly from the reaction between the added reactants or from an intermediate from one or more added reactants that can be obtained in the reaction mixture. The term "bringing into contact" may include allowing two particles to react, interact, or physically contact, where the two particles may be a compound as described herein and a protein or enzyme, such as a protein tyrosine phosphatase, such as protein- non-type 2 receptor tyrosine phosphatase (PTPN2) or non-type 1 protein tyrosine phosphatase (PTP1B).

As defined herein, the term "inhibition", "inhibit", "inhibition" and the like in relation to an inhibitor-protein (e.g., antagonist) interaction means a negative effect (e.g., reduction) in the activity or function of a protein as compared to the activity or function of the protein. in the absence of an inhibitor. In some embodiments, inhibition refers to the reduction of a disease or symptoms of a disease. In some embodiments of the invention, inhibition refers to a decrease in the activity of a signal transduction pathway or a signaling pathway. Thus, inhibition includes, at least in part, partial or complete blocking of stimulation, reduction, prevention or elimination of activation or inactivation, desensitization or suppression of signal transmission or enzymatic activity or amount of protein. In some embodiments, inhibition refers to a reduction in 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 (PTP1B). Thus, inhibition may include, at least in part, partial or complete reduction of stimulation, reduction or reduction of activation, or inactivation, desensitization or suppression of signaling or enzymatic activity or amount of protein tyrosine phosphatase, for example protein tyrosine phosphatase. non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B).

"Patient" or "subject in need thereof" refers to a living organism suffering from or predisposed 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, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the patient is a pet. 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 of the invention, the patient is cattle. In some embodiments, the patient is a dog. 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 neonate. In some embodiments, the patient is a neonatal mammal. In some embodiments, the patient is an old animal. In some embodiments, the patient is an elderly person. In some embodiments, the patient is an aged mammal. In some embodiments, the patient is a geriatric patient.

"Disease", "disorder", or "condition" refers to the general or health condition of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein include the reduction or elimination of one or more symptoms of a disease, disorder, or condition, for example, by administering a compound described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound, described herein, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The term "signaling pathway" as used herein refers to a series of interactions between cellular or optionally extracellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that transmit a change from one component to one or more other components that, in in turn, can communicate the change to additional components that do not necessarily propagate to components of other signaling pathways.

A "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refers to a substance that facilitates administration of the active agent to the subject and absorption of the active agent by the subject, and can be included in the compositions of the present invention without causing significant toxic side effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline, Ringer's lactate solution, sucrose, glucose, binder, 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 dyes, and the like. Such preparations may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, osmotic salts, buffers, colorants and/or flavors, and the like, which are not have harmful effects, with the compounds of this invention. The person skilled in the art will appreciate that other pharmaceutical excipients are suitable for this invention.

The term "preparation" is intended to include a dosage form of the active compound with an encapsulating material as a carrier, providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier, which is therefore in combination with it. Similarly, sachets and lozenges are included. Tablets, powders, capsules, pills, sachets and lozenges can be used as solid dosage forms suitable for oral administration.

In the context of this document, the term "administration" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or implantation of a slow-release device, such as a mini-osmotic pump, subject. Administration is by many routes, including parenteral or transmucosal (eg, 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 methods of delivery 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, immediately before or immediately after administration one or more additional therapies (eg, anti-cancer agent, chemotherapeutic or immunotherapeutic agent). The compounds or compositions described herein may be administered separately or may be administered simultaneously to a patient. Combined administration is intended to include the simultaneous or sequential administration of a compound or composition alone or in combination (more than one compound or agent). Also, if desired, the drugs can be combined with other active substances (eg, to reduce metabolic degradation).

In the context of this document, the term "PTPN2" refers to a protein tyrosine phosphatase that is not a type 2 receptor. The term "PTPN1" refers to a protein tyrosine phosphatase that is not a type 1 receptor (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B) ,

Connections

This document describes, for example, a compound of formula (I):

(I);

(I);

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N -oxide, stereoisomer or isotopically enriched variant thereof, wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, -N(R ^a )-C _1-6 alkyl and -C _1-6 alkylene -5-6 membered heterocyclyl;

where C _1-6 alkyl, C _3-6 cycloalkyl, -OC _1-6 alkyl, -N(R ^a )-C _1-6 alkyl and -C _1-6 alkylene-5-6 membered heterocyclyl may optionally be substituted at one or more available carbon atoms with one, two, three or more substituents each independently selected from R ^g ; and moreover, if -C _1-6 alkylene-5-6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

R ² is selected from the group consisting of hydrogen, hydroxyl, -CHF ₂ , -CH ₂ OH, -CH ₂ CN, -CH ₂ -OC _1-6 alkyl, -CH ₂ -N(R ^a )-C _1-6 alkyl, C _2-6 alkyl, C _2-6 alkenyl, -OC _1-6 alkyl, -N(R ^a )-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 , -N(R ^a )-C(O)-OC _1-6 alkyl, -C _3-6 cycloalkyl, -OC _3-6 cycloalkyl, C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkenylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -OC _1-6 alkylene-5-6 membered heteroaryl, -O-4 -6 membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene-4-6 membered heterocyclyl and -OC _1-6 alkylene-4-6 membered heterocyclyl;

where -CH ₂ -OC _1-6 alkyl, -CH ₂ -N(R ^a )-C _1-6 alkyl, C _2-6 alkyl, C _2-6 alkenyl, -OC _1-6 alkyl, -N(R ^a )-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, -N(R ^a )-C(O)-OC _1-6 alkyl, -C _3-6 cycloalkyl , -OC _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, -C _1-6 alkenylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, 5-6 membered heteroaryl, -OC _1-6 alkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, -O-4-6 membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene -4-6 membered heterocyclyl and -OC _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 moreover, if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(R ^a )-4-6 membered heterocyclyl, -C _1-6 alkylene-4-6 membered heterocyclyl or -OC _1-6 alkylene-4 -6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

or R ¹ and R ² taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted with one or more substituents each independently selected from the group consisting of halo, hydroxyl, cyano, C _1-6 alkyl and C _1-6 alkoxy; where C _1-6 alkyl and C _1-6 alkoxy may optionally be substituted with one, two, three or more substituents each independently selected from R ^P ;

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

where -C _1-6 alkyl, -OC _1-6 alkyl, -N(R ^a )-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 and -C _1-6 alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbon atoms one, two, three or more substituents each independently selected from R ^g ; and moreover, if -C _1-6 alkylene _-4-6 membered heterocyclyl contains a substituted ring nitrogen atom, this 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; where 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 moreover, if -C _1-6 alkylene-4-6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

where at least one of R ¹ , R ² , R ³ and R ⁴ is not hydrogen;

R ⁵ 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; where 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 moreover, if -C _1-6 alkylene-4-6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with R ^h ;

R ⁶ is hydrogen;

R ⁷ is hydrogen;

for each occurrence, R ^g is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, 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, phenyl, C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -(CO)-(NR ^a )-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 )-, 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 )-, 4-6 membered heterocyclyl-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-, -P(O)(C _1-3 alkyl) ₂ 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, phenyl, C _1-6 alkylene-C _3-6 cycloalkyl, -OC _1-6 alkylene-C _3-6 cycloalkyl, -(CO)-(NR ^a )-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 )-, 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 )-, 4-6 membered heterocyclyl-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-, -P(O)(C _1-3 alkyl) ₂ and C _1-6 alkoxy-C _1-6 alkyl- may optionally be substituted with one, two , three or more substituents each independently selected from R ^P ;

for each occurrence, R ^h is independently selected 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-C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ -, C _3-6 cycloalkyl-S(O) ₂ -, 4-6 membered heterocyclyl-S(O) ₂ -, 4-6 membered heterocyclyl-C _1-6 alkyl- S(O) ₂ -, 5-6 membered heteroaryl-S(O) ₂ -, phenyl-S(O) ₂ -, phenyl-C _1-6 alkyl-S(O) ₂ -, C _1-6 alkyl- C(O)-, C _1-6 cycloalkyl-C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)-, R ^a R ^b N-SO ₂ - and -P(O)(C _1-3 alkyl) ₂ ; where C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, C _3-6 cycloalkyl, -C _1-6 alkyl-C _3-6 cycloalkyl, C _1-6 alkyl-S(O) ₂ - , C _3-6 cycloalkyl-S(O) ₂ -, 4-6 membered heterocyclyl-S(O) ₂ -, 4-6 membered heterocyclyl-C _1-6 alkyl-S(O) ₂ -, 5-6 membered heteroaryl-S(O) ₂ -, phenyl-S(O) ₂ -, phenyl-C _1-6 alkyl-S(O) ₂ -, C _1-6 alkyl-C(O)-, C _1-6 cycloalkyl -C(O)-, C _1-6 alkoxy-C(O)-, R ^a R ^b NC(O)-, R ^a R ^b N-SO ₂ - and -P(O) (C _1-3 alkyl ) ₂ may optionally be substituted with one, two, three or more substituents each independently selected from R ^P ;

for each occurrence, R ^p is independently selected from the group consisting of halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, 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 )-;

for each occurrence, R ^a and R ^b are independently selected from the group consisting of hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl; where C _1-6 alkyl may optionally be substituted with one or more substituents, each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and C _1-6 alkoxy (optionally substituted with one, two or three fluorine atoms);

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

w is 0, 1, or 2.

In some embodiments, one, two, three or more hydrogen atoms of the compound may optionally be deuterium atoms; and wherein all other atoms of the compound are present in their natural isotopic composition. For example, in some embodiments, one, two, three, or more hydrogen atoms may optionally be deuterium atoms in one, two, three, or more groups, each independently selected from R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^g .

In some embodiments, R ¹ is selected from the group consisting of, for example, hydrogen, deuterium, chlorine, and fluorine.

In some embodiments, R ² is 4-6 membered heterocyclyl; where R ² may optionally be substituted on one or more available carbon atoms with one, two or three substituents, each independently selected from R ^g , and, if a 4-6 membered heterocyclyl contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with a substituent selected from R ^h . For example, in some embodiments, R ² is 4-6 membered heterocyclyl; where R ² may optionally be substituted on one or more available carbon atoms with one, two or three substituents, each independently selected from the group consisting of hydrogen and C _1-6 alkyl; and wherein if R ² contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted with a substituent selected from the group consisting of hydrogen, C _1-6 alkyl (optionally substituted with one, two or three fluorine atoms), -C _{1- 6} alkyl-C _3-6 cycloalkyl, C _1-6 cycloalkyl-C(O)-, C _1-6 alkyl-S(O) ₂ - (optionally substituted with cyano, methoxy or one, two or three fluorine atoms), C _3-6 cycloalkyl-S(O) ₂ -, 4-6 membered heterocyclyl-S(O) ₂ -, 4-6 membered heterocyclyl-C _1-6 alkyl-S(O) ₂ -, 5-6 membered heteroaryl- S(O) ₂ -, phenyl-S(O) ₂ -, phenyl-C _1-6 alkyl-S(O) ₂ -(optionally substituted R ^a R ^b N-), and -P(O)(C _{1 -3} alkyl) ₂ . For example, in some embodiments, R ² is selected from the group consisting of, for example:

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In other embodiments, R ² is 5-6 membered heteroaryl; where R ² may optionally be substituted on one or more available carbon atoms with one, two or three substituents each independently selected from R ^g , and wherein, if R ² contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted a substituent selected from R ^h . For example, in some embodiments, R ² is 5-6 membered heteroaryl; where R ² may optionally be substituted on one or more available carbon atoms with one, two or three substituents each independently selected from the group consisting of hydrogen, cyano, C _1-6 alkyl, C _1-6 alkoxy and -P( O)(C _1-3 alkyl) ₂ ; and moreover, if R ² contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of hydrogen, -C _1-6 alkyl-C _3-6 cycloalkyl and C _3-6 cycloalkyl-S (O) _2- . For example, in some embodiments, R ² is selected from the group consisting of, for example:

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In additional embodiments, R ² is -OC _1-6 alkylene-4-6 membered heterocyclyl, where R ² may optionally be substituted on one or more available carbon atoms with one, two, or three substituents each independently selected from R ^g , and moreover, if R ² contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted with a substituent selected from R ^h . For example, in some embodiments, R ² is -OC _1-6 alkylene-4-6 membered heterocyclyl, where R ² may optionally be substituted on one or more available carbon atoms with one, two, or three substituents, each independently selected from the group consisting of hydrogen, halogen and C _1-6 alkyl, and moreover, if R ² contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 alkyl-S(O) ₂ -. For example, in some embodiments, R ² is selected from the group consisting of, for example:

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In other embodiments, R ² is -OC _1-6 alkylene-5-6 membered heteroaryl. For example, in some embodiments, R ² is selected from the group consisting of, for example:

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And

.

In additional embodiments, R ² is selected from the group consisting of -C _2-6 alkyl, C _2-6 alkenyl, and C _3-6 cycloalkyl; where R ² may optionally be substituted with one, two, three or more substituents, each independently selected from R ^g . For example, in some embodiments, R ² is selected from the group consisting of -C _2-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, -C _1-6 alkylene-C _3-6 cycloalkyl, and -C _{1- 6} alkenylene-C _3-6 cycloalkyl; where R ² may optionally be substituted with one, two, three or more substituents, each independently selected from the group consisting of cyano, chlorine, fluorine, hydroxyl, C _1-6 alkoxy, phenyl, and R ^a R ^b N-. For example, in some embodiments, R ² is selected from the group consisting of, for example:

In other embodiments, R ² is -OC _1-6 alkyl; where R ² may optionally be substituted with one, two, three or more substituents, each independently selected from R ^g . For example, in some embodiments, R ² is -OC _1-6 alkyl; where R ² may optionally be substituted with one, two, three or more substituents, each independently selected from the group consisting of cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, C _1-6 alkoxy, C _3-6 cycloalkoxy, -OC _1-6 alkylene-C _3-6 cycloalkyl, -(CO)-(NR ^a )-C _1-6 alkylene-C _3-6 cycloalkyl, C _1-6 alkyl-OC(O)-, R ^a R ^b N - (wherein R ^b is optionally substituted with -OCH ₃ or -OCF ₃ ), C _1-6 alkyl-N(R ^a )-, R ^a R ^b NC(O)-, -P(O)(C _1-3 alkyl ) ₂ , C _1-6 alkyl-N(R ^a )-C(O)-, C _1-6 alkyl-N(R ^a )-C(O)-N(R ^a )-, C _1-6 alkyl -SO ₂ -N(R ^a )-, C _3-6 cycloalkyl-SO ₂ -N(R ^a )- and 4-6 membered heterocyclyl-SO ₂ -N(R ^a )-. For example, in some embodiments, R ² is selected from the group consisting of, for example:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

.

In other embodiments, R ² is -OC _3-6 cycloalkyl or -O-4-6 membered heterocyclyl; wherein if R ² contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted with a substituent selected from R ^h . For example, in some embodiments, R ² is -OC _3-6 cycloalkyl or -O-4-6 membered heterocyclyl; moreover, if R ² contains a substituted ring nitrogen atom, this ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of C _1-6 alkyl-SO ₂ -N(R ^a )- and C _3-6 cycloalkyl-SO ₂ -N(R ^a )-. For example, in some embodiments, R ² is selected from the group consisting of, for example:

,

,

и

.

,

,

And

.

In still other embodiments, R ² is -N(R ^a )-C _1-6 alkyl, where R ² may optionally be substituted with one, two, or three substituents each independently selected from R ^g . For example, in some embodiments, R ² is -N(R ^a )-C _1-6 alkyl, where R ² may optionally be substituted with one, two, or three substituents, each independently selected from the group consisting of fluorine, -C( O)OH, cyano, oxo, R ^a R ^b N-, C _1-6 alkoxy, phenyl, -C _3-6 cycloalkyl, C _3-6 cycloalkyl-SO ₂ -N(R ^a )- and -(CO) -(NR ^a )-C _1-6 alkylene-C _3-6 cycloalkyl. For example, in some embodiments, R ² is selected from the group consisting of, for example:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

.-N(H)CH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

.

,

,

,

,

,

,

,

,

,

,

,

,

,

и

.In other embodiments, R ² is -OC _1-6 alkylene-C _3-6 cycloalkyl, where R ² may optionally be substituted with one, two, or three substituents each independently selected from R ^g . For example, in some embodiments, R ² is -OC _1-6 alkylene-C _3-6 cycloalkyl, where R ² may optionally be substituted with one, two, or three substituents, each independently selected from the group consisting of fluorine, hydroxyl, R ^a R ^b N-, cyano and C _1-3 alkyl; where C _1-3 alkyl may be optionally substituted with a substituent selected from the group consisting of cyano and C _1-3 alkoxy. For example, in some embodiments, R ² is selected from the group consisting of, for example:

,

,

,

,

,

,

,

,

,

,

,

,

,

And

.

.In some embodiments, R ² is -OC(O)-N(R ^a )-C _1-6 alkyl. For example, in some embodiments, R ² is represented by, for example:

.

In additional embodiments, R ² is —N(R ^a )-4-6 membered heterocyclyl, wherein if R ² contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted with a substituent selected from R ^h . For example, in some embodiments, R ² is -N(R ^a )-4-6 membered heterocyclyl, wherein if R ² contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted with a substituent selected from the group consisting of C _1-6 alkyl-SO ₂ -N(R ^a )- and C _3-6 cycloalkyl-SO ₂ -N(R ^a )-. For example, in some embodiments, R ² is selected from the group consisting of, for example:

,

,

и

.

,

,

And

.

In other embodiments, R ² is -C _1-6 alkylene-4-6 membered heterocyclyl, wherein if R ² contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted with a substituent selected from R ^h . For example, in some embodiments, R ² is -C _1-6 alkylene-4-6 membered heterocyclyl, wherein if R ² contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted with a substituent selected from the group consisting of C _1-6 alkyl, C _1-6 alkyl-SO ₂ -N(R ^a )- and C _3-6 cycloalkyl-SO ₂ -N(R ^a )-, where C _1-6 alkyl may optionally be substituted with one, two or three fluorine atoms. For example, in some embodiments, R ² is selected from the group consisting of, for example:

,

,

,

,

,

,

и

.

,

,

,

,

,

,

And

.

In some embodiments, R ² is selected from the group consisting of, for example,

и

. -CHF ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CN, -OH,

And

.

In some embodiments, R ¹ and R ² taken together with the atoms to which they are attached form a 5 membered heteroaryl. For example, in some embodiments, R ¹ and R ² taken together with the atoms to which they are attached form, for example, furanyl. For example, in some embodiments, a compound of formula (I) is:

.

.

In some embodiments, R ³ is hydrogen. In other embodiments, R ⁴ is hydrogen. In additional embodiments, R ⁵ is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine. In other embodiments, R ⁶ is selected from the group consisting of hydrogen and deuterium. In additional embodiments, R ⁷ is selected from the group consisting of hydrogen and deuterium. In some embodiments, all atoms of the compound of formula (I) are present in their natural isotopic composition.

This document also describes the compound represented by formula (II):

(II)

(II)

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N -oxide or stereoisomer thereof, wherein:

X is selected from the group consisting of -O- and -N(R ^a )-;

L is straight or branched C _1-6 alkylene;

R ^2-II is selected from the group consisting of hydrogen, cyano, -NR ^a R ^b , C _1-2 alkoxy, C _3-6 cycloalkyl-SO ₂ -N(R ^a )-, C _1-6 alkyl-SO ₂ -N(R ^a )-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C _3-6 cycloalkyl; wherein phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C _3-6 cycloalkyl may optionally be substituted on one or more available carbon atoms with one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NR ^a R ^b , C _1-2 alkyl (optionally substituted with one, two or three halogens) and C _1-2 alkoxy (optionally substituted with one, two or three halogens); and wherein, if the 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be substituted with C _1-3 alkyl;

R ⁵ is selected from the group consisting of hydrogen, deuterium and halogen;

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

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

for each occurrence, each R ^a and R ^b is independently selected from the group consisting of hydrogen and C _1-3 alkyl.

In some embodiments, X is selected from the group consisting of -O-, -N(H)- and -N(CH ₃ )-.

In other embodiments, L is selected from the group consisting of

,

,

,

,

и

; где * и # представляют собой ковалентные точки присоединения к R^2-II и X, соответственно.

,

,

,

,

And

; where * and # represent the covalent points of attachment to R ^2-II and X, respectively.

,

,

,

,

,

,

,

,

,

,

и

. In additional embodiments, R ^2-II is selected from the group consisting of: hydrogen, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -OCH ₃ ,

,

,

,

,

,

,

,

,

,

,

And

.

In some embodiments, R ⁵ is selected from the group consisting of hydrogen, deuterium, and fluorine.

This document also describes the compound represented by formula (III):

(III);

(III);

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N -oxide or stereoisomer thereof, wherein:

X ^III is selected from the group consisting of bond, -CH ₂ -, -NR ^a -, -O-, -O-CH ₂ - and -OCH ₂ -CH ₂ -

m is 1, 2 or 3;

n is 1, 2 or 3;

R ^1-III is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR ^a R ^b , C _1-2 alkyl (optionally substituted with one, two or three halogens) and C _1-2 alkoxy (optionally substituted with one, two or three halogens);

R ^2-III is selected from the group consisting of hydrogen, C _1-4 alkyl, -C(O)-C _1-4 alkyl, -C(O)-OC _1-4 alkyl, -C(O)-N( R ^a )-C _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -C _3-6 cycloalkyl; where C _1-4 alkyl, -C(O)-C _1-4 alkyl, -C(O)-OC _1-4 alkyl, -C(O)-N(R ^a )-C _1-4 alkyl, - S(O) ₂ -C _1-4 alkyl and -S(O) ₂ -C _3-6 cycloalkyl may optionally be substituted with one, two or three substituents, each independently selected from the group consisting of halogen, hydroxyl, cyano, - NR ^a R ^b , C _1-2 alkyl (optionally substituted with one, two or three halogens) and C _1-2 alkoxy (optionally substituted with one, two or three halogens);

R ⁵ is selected from the group consisting of hydrogen, deuterium and halogen;

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

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

for each occurrence, each R ^a and R ^b is independently selected from the group consisting of hydrogen and C _1-3 alkyl.

In some embodiments, X ^III is selected from the group consisting of a bond, -CH ₂ , -O-, -NH- and -O-CH ₂ -.

In other embodiments, R ^2-III is selected from the group consisting of hydrogen, isopropyl, -CH ₂ CF ₃ , -S(O) ₂ -CH ₃ and -S(O) ₂ -cyclopropyl.

In additional embodiments, R ⁵ is selected from the group consisting of hydrogen, deuterium and fluorine.

The compound further described herein is selected from the group consisting of:

5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione; 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl propan-2-ylcarbamate;

5-(9-fluoro-7-hydroxynaphtho[2,1- b ]furan-8-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione; 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-methoxy( ^4-2 H)naphthalen-2-yl]( ^4,4-2 H ₂ )-1λ ^6,2,5 -thiadiazolidin-1,1,3 -trione;

5-[1-fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile;

5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile ;

5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[( ² H ₃ )methyloxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile ;

5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione;

5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)( ^4,4-2 H ₂ )-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide ;

5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile;

[1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl] acetonitrile;

5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropylmethyl)-1 H -pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{1-fluoro-3-hydroxy-7-[( 1H- pyrazol-4-yl)methoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-[1-fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione;

5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3 S )-3-hydroxybutoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3 R )-3-hydroxybutoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4 R )-4-hydroxypentyl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4 R )-4-hydroxypentyl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(4 S )-4-hydroxypentyl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-{1-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

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

1-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropane -1-carbonitrile;

5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

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

5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}butanenitrile;

5-[1-fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-{1-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}methyl)cyclopropan-1 -carbonitrile;

5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[3-(1 H -pyrazol-1-yl)propoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-(7-{1-[(4-Aminophenyl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(1 H -pyrazol-1-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(piperidin-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-(7-{1-[(2-Aminophenyl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropan-1 -carbonitrile;

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

5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetonitrile;

5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

(2 E )-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]prop-2- ennitrile;

5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2- tert -Butoxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[ rac -(1 R ,2 R )-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1, 3-trione;

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

5-{7-[3-(2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(4-methyl-1 H -imidazol-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-[7-(azetidin-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetonitrile;

5-[1-fluoro-3-hydroxy-7-(methoxymethyl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione;

5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3 S )-pyrrolidin-3-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(3 R )-pyrrolidin-3-yl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(8-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

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

5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-(4-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[( E )-2-cyclopropylethenyl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(1 E )-4-methylpent-1-en-1-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ^6,2,5- thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(1 E )-3-methoxyprop-1-en-1-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(1,1-dioxo-1λ ⁶ -thian-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{2-[methyl(2-methylpropyl)amino]ethoxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-{1-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-(7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-[1-fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-{1-fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(3,6-dihydro-2 H -pyran-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[7-(2,5-dihydro-1 H -pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[1-fluoro-3-hydroxy-7-(pyridin-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(azetidin-3-yl)methyl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

N -(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] amino}acetamide;

4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} -N -methylbutanamide;

N -ethyl- N '-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] hydroxy}ethyl)urea;

5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[(1-chloro-3-hydroxypropan-2-yl)oxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{1-fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalene-2-yl}-1λ ⁶ , 2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3,7-dihydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[1-fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-propoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

{[8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetic acid;

N -(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] hydroxy}acetamide;

N, N -diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} acetamide;

5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione;

5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-{1-fluoro-3-hydroxy-7-[1-(oxolane-3-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2.5 -thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropan-1-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl }-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropan-1-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl }-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{1-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}naphthalene-2-yl)-1λ ^6,2,5 -thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(4,4,4-trifluorobutan-1-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl }-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(butan-1-sulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione;

5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro- 1H- pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl )-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]-2,5-dihydro -1 H -pyrrole-1-sulfonyl}pentanenitrile;

5-{1-fluoro-3-hydroxy-7-[1-(pentan-2-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione;

N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)oxetane -3-sulfonamide;

5-[1-fluoro-3-hydroxy-7-(piperidin-4-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(2-methylpropan-1-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-(7-ethoxy-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(cyclopropanesulfonyl)-1 H -pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-(1-fluoro-3-hydroxy-7-{[(3 R )-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione;

5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ;

5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione;

5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(1,3-dimethyl- 1H -pyrazole-4-sulfonyl)-2,5-dihydro- 1H- pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2 -yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)ethanesulfonamide ;

5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]-3-hydroxynaphthalene-2-yl}-1λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutan-1-sulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

5-{1-fluoro-3-hydroxy-7-[1-(thiophene-3-sulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]naphthalene-2-yl}-1λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione;

5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione;

methyl (2 S )-2-amino-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2- yl]hydroxy}butanoate;

5-{7-[(3,5-dimethyl-1 H -pyrazol-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trion;

5-[7-(3,5-dimethyl-1 H -pyrazol-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione;

5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione;

2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-1 H -imidazole-4-carbonitrile ;

and a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N -oxide or stereoisomer thereof.

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is formulated as a pharmaceutically acceptable composition comprising the described compound and a pharmaceutically acceptable carrier.

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is selected from a compound listed in Table 1.

Table 1: Illustrative examples of compounds according to this invention.

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

231A

231B

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

Methods for preparing exemplary compounds

Compounds The present disclosure may be better understood by the following synthetic schemes and methods, which illustrate the routes by which compounds may be prepared. The compounds of the present invention may be prepared by a variety of synthetic procedures. Typical synthesis methods are illustrated, but not limited to, in Schemes 1-7. The variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are defined as detailed herein, ie in the Summary of the Invention.

Scheme 1: Typical scheme for the synthesis of illustrative compounds according to this invention.

As illustrated in Scheme 1, compounds of formula (1-9), formula (1-10), formula (1-11) and formula (1-12) can be obtained from compounds of formula (1-1). Compounds of formula (1-1) may be alkylated with an optionally substituted benzyl bromide (eg benzyl bromide, 4-methoxybenzyl bromide or 3,4-dimethoxybenzyl bromide) in the presence of a base such as cesium carbonate in a solvent such as N,N -dimethylformamide. The carboxyl group also reacts under these conditions to form the benzyl ester. The benzyl ester can be hydrolyzed with a base such as lithium hydroxide or sodium hydroxide in methanol or a mixture of methanol and water to give compounds of formula (1-2). Compounds of formula (1-2) may react under Curtius reaction conditions (diphenylphosphorazidate, t -butanol, triethylamine in heated toluene) to form compounds of formula (1-3). the tert -Butoxycarbonyl moiety can be removed from compounds of formula (1-3) by treatment with heated diethylenetriamine to give compounds of formula (1-4). Compounds of formula (1-4) may be reacted with 2-bromoacetates of formula (1-5) in the presence of a base such as potassium carbonate in a heated solvent such as, but not limited to, a mixture of N,N -dimethylformamide and water to form compounds of formula (1-6). Compounds of formula (1-6) can then be fluorinated with a reagent such as N -fluorobenzenesulfonimide (NFSI) in a solvent such as tetrahydrofuran or Selectfluor® in optionally heated N,N -dimethylformamide to form compounds of formula (1-7). Compounds of formula (1-7) may be reacted with chlorosulfonyl isocyanate and tert -butanol in the presence of a tertiary amine base such as triethylamine in a solvent such as chilled dichloromethane. Subsequent treatment under acidic conditions, such as trifluoroacetic acid in dichloromethane, to remove the t -butoxycarbonyl group gives compounds of formula (1-8). Compounds of formula (1-8) may be reacted with an alkoxide base such as sodium methoxide in optionally heated methanol or a mixture of methanol and water or potassium t -butoxide in tetrahydrofuran and then quenched with an acid such as 1M hydrochloric acid with obtaining compounds of formula (1-9) or formula (1-10). Compounds of formula (1-9) can be converted to compounds of formula (1-11) with water under cross-coupling reaction conditions such as water in the presence of a pre-catalyst, RockPhos Pd G3, base, cesium carbonate and warm solvent, N, N -dimethylformamide. The optionally substituted benzyl ester of compounds of formula (1-10) can be removed under conditions known to the person skilled in the art and dependent on the particular benzyl ester. For example, the unsubstituted benzyl ester can be removed by treatment with trichloroborane in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane at -60 to -80°C to give compounds of formula (1-12). Compounds of formula (1-12) are compounds of formula (I).

Scheme 2: Typical scheme for the synthesis of illustrative compounds according to this invention.

As illustrated in Scheme 2, compounds of formula (2-2), formula (2-4), formula (2-6) and formula (2-8) can be obtained from compounds of formula (1-9). Compounds of formula (1-9) may be reacted under C-cross coupling reaction conditions. For example, Suzuki reaction conditions can be used to couple compounds of formula (1-9) with compounds of formula (2-1) where A is an alkene moiety, cyclopropyl, or an aromatic or partially unsaturated ring. Reaction conditions for coupling compounds of formula (1-9) with compounds of formula (2-1) may include a catalyst (tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, or [1,1'-bis(di- tert -butylphosphino)ferrocene]palladium (II) dichloride), and a base (sodium carbonate, potassium carbonate or cesium carbonate) in heated dioxane, a mixture of dioxane and water, or a mixture of tetrahydrofuran and water. Subsequently, the optionally substituted benzyl ester protecting group may be removed under conditions known to the person skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ether can be removed by treatment with trichloroborane in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane at -60 to -80°C to give compounds of formula (2-2). In addition, the unsubstituted benzyl ether can be removed by treatment with hydrogen and a palladium catalyst in a solvent such as dioxane or tetrahydrofuran. The compounds of formula (2-2) or the protected precursor may be further modified as is known to the person skilled in the art and illustrated in the Examples.

Compounds of formula (1-9) may be reacted under N-cross-coupling reaction conditions. For example, Buchwald-Hartwig reaction conditions can be used to couple compounds of formula (1-9) with compounds of formula (2-3). For example, compounds of formula (1-9) and compounds of formula (2-3) can be cross-coupled in the presence of a pre-catalyst (BrettPhos Pd G3 or RuPhos Pd G3) or a catalyst (palladium (II) acetate), a ligand (BrettPhos , RuPhos or Xantphos), and a base (sodium t -butoxide or cesium carbonate) in a heated solvent such as dioxane or t -amyl alcohol. Subsequently, the optionally substituted benzyl ether protecting group can be removed as described above to give compounds of formula (2-4) wherein NR ^2-1 R ^2-2 is a cyclic or acyclic R ² moiety. The compounds of formula (2-4) or the protected precursor may be further modified as is known to the person skilled in the art and illustrated in the Examples.

Compounds of formula (1-9) may be reacted under O-cross-coupling reaction conditions. For example, cross-coupling reaction conditions can be used to couple compounds of formula (1-9) with compounds of formula (2-5). For example, compounds of formula (1-9) and compounds of formula (2-5) may be coupled in the presence of a RockPhos Pd G3 precatalyst and a base, cesium carbonate, in a heated solvent such as N,N -dimethylformamide. Subsequently, the optionally substituted benzyl ether protecting group can be removed as described above to give compounds of formula (2-6) wherein OR ^2-3 is the ether moiety of R ² . The compounds of formula (2-6) or the protected precursor may be further modified as is known to those skilled in the art and illustrated in the Examples.

Compounds of formula (1-9) may be reacted under C-cross-coupling reaction conditions. For example, compounds of formula (1-9) may be cross-coupled with allyl compounds of formula (2-7) where R ^2-4 is an R ² residue outside the allyl moiety. Reaction conditions for cross-coupling compounds of formula (1-9) with compounds of formula (2-7) may include a catalyst such as palladium(II) acetate, a phosphine ligand such as 2-(di - tert-butylphosphino ) biphenyl, 2 -dicyclohexylphosphino - 2 ', 6' - dimethoxybiphenyl or 4,5-bis(diphenylphosphino) -9,9 -dimethylxanthene and a base such as a tertiary amine base such as triethylamine or cesium carbonate in a heated solvent such as N , N -dimethylformamide or dioxane. Subsequently, the optionally substituted benzyl ester protecting group may be removed as described above to give compounds of formula to give compounds of formula (2-8). The compounds of formula (2-8) or the protected precursor may be further modified as known to those skilled in the art and illustrated in the Examples.

Compounds of formula (2-2), formula (2-4), formula (2-6) or formula (2-8) are compounds of formula (I) or are precursors of compounds of formula (I).

Scheme 3: Typical scheme for the synthesis of illustrative compounds according to this invention.

As illustrated in Scheme 3, compounds of formula (3-1) and formula (3-2) can be obtained from compounds of formula (1-11). Compounds of formula (1-11) may be alkylated with compounds of formula R ^3-1 -LG ¹ where LG ¹ is a leaving group such as chlorine, bromine, iodo or sulfonate and R ^3-1 is optionally substituted alkyl, optionally substituted heterocyclyl; or optionally substituted cycloalkyl. Alkylation conditions may include, but are not limited to, treatment with a base such as cesium carbonate or sodium hydride in an optionally heated solvent such as N,N -dimethylformamide. Subsequently, the optionally substituted benzyl ester protecting group may be removed under conditions known to the person skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ester can be removed by treatment with trichloroborane in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane at -60 to -80°C to give compounds of formula (3-1). The compounds of formula (3-1) or the corresponding protected precursors may be further modified as known to those skilled in the art and illustrated in the Examples. The OR ^3-1 group is the ether fragment of R ² .

An alternative method for preparing compounds of formula (3-1) involves reacting compounds of formula (1-11) with compounds of formula R ^3-1 -OH, where R ^3-1 is optionally substituted alkyl or optionally substituted cycloalkyl under Mitsunobu reaction conditions. Suitably, compounds of formula (1-11) and compounds of formula R ^3-1 -OH can be treated with ( E )-diazene-1,2-diylbis(piperidin-1-ylmethanone) and tri- p -butylphosphine in a solvent such as heated tetrahydrofuran. Subsequent removal of the benzyl protecting group as described above gives compounds of formula (3-1). Compounds of formula (3-1) or corresponding protected precursors may be further modified as is known to those skilled in the art and illustrated in the Examples.

Compounds of formula (1-11) can also be converted to compounds of formula (3-2). Compounds of formula (1-11) may be reacted with compounds of formula R ^3-2 -NCO, where R ^3-2 is an optionally substituted C _1-6 alkyl, in the presence of 4-dimethylaminopyridine in a solvent such as N, N -dimethylformamide, with the formation of the corresponding carbamate. Subsequent removal of the benzyl protecting group as described above gives compounds of formula (3-2). The -OC(O)NHR ^3-2 group is the R ² carbamate group. The compounds of formula (3-2) or the corresponding protected precursors may be further modified as is known to the person skilled in the art and illustrated in the Examples.

The compounds of formula (3-1) and formula (3-2) are compounds of formula (I) or are precursors of compounds of formula (I).

Scheme 4: Typical scheme for the synthesis of illustrative compounds according to this invention.

As shown in Scheme 4, compounds of formula (4-4) can be obtained from compounds of formula (1-9). Compounds of formula (1-9) can be reacted under cross-coupling reaction conditions with a boron-containing reagent of formula (4-1), such as bis(pinacolato)dibor, where one R ^B is connected to another R ^B , to give a compound of formula (4-2). Reaction conditions for cross-coupling compounds of formula (1-9) with compounds of formula (4-1) may include a catalyst ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed with dichloromethane) and a base (potassium acetate or potassium carbonate) in heated dioxane. Compounds of formula (4-2) may subsequently be linked to compounds of formula (4-3) wherein R ^{2 -C} is an aromatic or partially unsaturated ring, an alkyl group, or an alkyl group and LG ² is a leaving group such as iodo , bromine or chlorine. Reaction conditions for cross-coupling compounds of formula (4-4) with compounds of formula (4-3) may include a catalyst (tetrakis(triphenylphosphine)palladium (0), XPhos Pd G2 or meCgpPh Pd G3) and a base (sodium carbonate, potassium phosphate or potassium carbonate) in a heated mixture of toluene and ethanol or dioxane and water, or N -methyl-2-pyrrolidinone. Subsequently, the optionally substituted benzyl ester protecting group may be removed under conditions known to the person skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ester can be removed by treatment with trichloroborane in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane at -60 to -80°C to give compounds of formula (4-4). The compounds of formula (4-4) or the corresponding protected precursors may be further modified as is known to the person skilled in the art and illustrated in the Examples.

Compounds of formula (4-4) are compounds of formula (I) or are precursors of compounds of formula (I).

Scheme 5: Typical scheme for the synthesis of illustrative compounds according to this invention.

As shown in Scheme 5, compounds of formula (5-3) can be obtained from compounds of formula (1-9). Compounds of formula (1-9) can be cross-coupled with compounds of formula (5-1) wherein R ^PR is a potassium trifluoroborate or carboxylic acid group and where B is an optionally substituted heterocyclyl or an optionally substituted alkyl in photoredox - conditions. Cross-coupling reaction conditions of compounds of formula (1-9) and compounds of formula (5-1) are treatment with NiCl ₂ adduct of dimethoxyethane, ligand (4,4'-di -tert -butyl-2,2'-dipyridyl), base (cesium carbonate) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium (1+); 2-(2-pyridyl)pyridine; hexafluorophosphate in solvents such as dioxane with optional N,N -dimethylacetamide in a 450 nm LED photoreactor. Subsequently, the optionally substituted benzyl ester protecting group may be removed under conditions known to the person skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ester can be removed by hydrogenation in the presence of a palladium-carbon catalyst in tetrahydrofuran to give compounds of formula (5-3).

Alternatively, the reaction conditions described above also allow compounds of formula (5-1) to be combined with compounds of formula (5-2) wherein PG ³ is (2-methoxyethoxy)methyl. Deprotection of one or both of the protecting groups can be achieved by treatment with hydrogen chloride in dioxane to give compounds of formula (5-3).

The compounds of formula (5-3) or the corresponding protected precursors may be further modified as is known to the person skilled in the art and illustrated in the Examples.

Compounds of formula (5-3) are compounds of formula (I) or are precursors of compounds of formula (I).

Scheme 6: Typical scheme for the synthesis of illustrative compounds according to this invention.

As shown in Scheme 6, compounds of formula (6-3) can be obtained from compounds of formula (6-1). Compounds of formula (6-1) wherein PG ¹ is a protecting group such as (2-methoxyethoxy)methyl and PG ² is an optionally substituted benzyl group or (2-methoxyethoxy)methyl can be linked to compounds of formula (6-2 ), where R ^6-1 represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group. Conditions for cross-coupling compounds of formula (6-1) with compounds of formula (6-2) are catalyzed (Pd SPhos G4) in heated N,N -dimethylacetamide. When present, the optionally substituted benzyl ester protecting group may be removed under conditions known to the person skilled in the art and dependent on the particular benzyl ester. For example, the unsubstituted benzyl ether (PG ² ) can be removed by hydrogenation in the presence of a palladium-carbon catalyst or by treatment with trichloroborane in dichloromethane to give compounds of formula (6-3). When both PG ¹ and PG ² represent a (2-methoxyethoxy)methyl group, one or both can be removed by treatment with an acid such as hydrogen chloride in dioxane to give compounds of formula (6-3). Compounds of formula (6-3) or corresponding protected precursors may be further modified as is known to those skilled in the art and illustrated in the Examples.

Compounds of formula (6-3) are compounds of formula (I) or are precursors of compounds of formula (I).

Scheme 7: Typical scheme for the synthesis of illustrative compounds according to this invention.

As illustrated in Scheme 7, compounds of formula (2-2) can be prepared from compounds of formula (1-9) in the reverse synthesis sequence of Scheme 2. In the first step, the optionally substituted benzyl moiety can be removed under conditions known to a person skilled in the art and dependent on the particular benzyl ester. For example, the unsubstituted benzyl ester can be removed by treatment with trichloroborane in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane at -60 to -80°C to give compounds of formula (7-1). Compounds of formula (7-1) may be reacted under C-cross coupling reaction conditions. For example, Suzuki reaction conditions can be used to couple compounds of formula (7-1) with compounds of formula (2-1) where A is an alkene moiety, cyclopropyl, or an aromatic or partially unsaturated ring. The corresponding boronic acids of the compounds of formula (2-1) are also suitable for cross-coupling. Reaction conditions for cross-coupling compounds of formula (7-1) with compounds of formula (2-1) may include a catalyst (1,1'-bis(di- tert -butylphosphino)ferrocene, palladium dichloride) and a base (sodium carbonate or potassium carbonate ) in heated dioxane or a mixture of dioxane and water. The compounds of formula (2-2) or the corresponding protected precursors may be further modified as known to those skilled in the art and illustrated in the Examples.

Compounds of formula (2-2) are compounds of formula (I) or are precursors of compounds of formula (I).

Pharmaceutical compositions

In the present description presents pharmaceutical compositions containing the compound described in this document, for example, the compound of formula (I), formula (II) or formula (III). In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is contained in an effective amount in a pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In certain embodiments of the invention, the effective amount is a prophylactically effective amount.

The pharmaceutical compositions described herein can be obtained by any method known in the field of pharmacology. Typically, such methods of preparation include the steps of bringing into association the described compound ("active ingredient") with a carrier and/or one or more other auxiliary ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into the desired one- or multi-dose unit. Pharmaceutical compositions may be prepared, packaged and/or sold in bulk, as a unit dose and/or as unit doses. The term "unit dose" as used herein is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that is administered to the subject and/or a convenient fraction of that dosage, such as, for example, half or one third of that dosage.

The relative amounts of a compound described herein, for example, 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 description will vary depending on the individual, the size and/or condition of the subject being treated, and further depending on the route of administration of the composition. As an example, the composition may contain from 0.1 to 100% (wt./wt.) of the compounds described in this document.

The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent or carrier that does not interfere with the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable adjuvants used in the manufacture of the pharmaceutical compositions of the invention are any of those well known in the pharmaceutical composition and include inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricants and/or oils. Pharmaceutically acceptable excipients used in the preparation of the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

Compositions of the present invention may 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 of the invention, the proposed compounds or compositions are administered intravenously and/or orally.

As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional, and intracranial injections or infusions. Preferably the compositions are administered orally, subcutaneously, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be in the form of an aqueous or oily suspension. These suspensions may be prepared according to methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be in the form of a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils have traditionally been used as a solvent or suspending medium.

Pharmaceutically acceptable compositions of this invention may 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, carriers commonly used include lactose and cornstarch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are needed for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may be added. In some embodiments, the proposed oral composition is formulated for immediate release or sustained/sustained release. In some embodiments

the composition is suitable for buccal or sublingual administration, including tablets, lozenges and lozenges. The compound described herein may also be in microencapsulated form.

The compositions of this invention can be delivered transdermally, topically, as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, suspensions, suspensions, etc., suitable for ingestion by a patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions and emulsions, for example water or water/propylene glycol solutions. Compositions of the present invention may 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 US patent No. 4911920; 5403841; 5,212,162 and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. Compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, 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 and injectable gel formulations (see , for example, Gao Pharm. Res. 12:857-863, 1995), or as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol . 49:669-674, 1997). implementation of the invention, the formulations of the compositions of the present invention can be delivered using liposomes that fuse with the cell membrane or are endocytosed, for example, using receptor ligands attached to the liposome that bind to receptors for proteins on the surface membrane of the cell, resulting in endocytosis. especially where the liposomal surface carries target cell-specific receptor ligands, or is otherwise preferentially targeted to a specific organ, delivery of the compositions of the present invention to target cells in vivo can be focused. (See, for example, 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 invention can also be delivered in the form of nanoparticles.

Alternatively, pharmaceutically acceptable compositions of this invention may be administered as rectal suppositories. Pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the target of treatment includes areas or organs that are easily accessible through topical application, including diseases of the eyes, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

In some embodiments, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered dosage form is accomplished by dissolving or suspending the drug in an oil vehicle.

While the descriptions of pharmaceutical compositions provided herein are generally directed to pharmaceutical compositions that are suitable for administration to humans, one of ordinary skill in the art will recognize that such compositions are generally suitable for administration to animals of all kinds. Modification of pharmaceutical compositions suitable for administration to humans to make compositions suitable for administration to various animals is well understood, and such modification can usually be designed and/or performed by a skilled veterinary pharmacologist using routine experimentation.

The compounds provided herein, for example, a compound of Formula (I), Formula (II), or Formula (III), are typically formulated in unit dosage form, eg, unit dosage form, for ease of administration and dosage uniformity. However, it should be understood that the overall daily use of the compositions of the present invention will be decided by the attending physician within the scope of a reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on a variety of factors, including the treatment of the disease and the severity of the disease; the activity of the specific active ingredient used; the specific composition used; 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 used; duration of treatment; preparations used in combination with or identical to the particular active ingredient used; and similar factors well known in medicine.

The exact amount of a compound needed 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 side effects or disorder, the identity of the particular compound(s), route of administration, and the like. . The desired dose can be delivered three times a day, twice a day, once a day, 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 routes of administration (eg, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

It is understood that the dosage ranges as described herein provide guidance for administering the provided pharmaceutical compositions to adults. The amount to be administered to, for example, a child or adolescent may be determined by the practitioner or one of skill in the art and may be lower or identical to that administered to an adult.

It will also be appreciated that a compound or composition described herein may be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions may be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and/or alter their metabolism, inhibit their excretion, and/or alter their distribution in the body. It will also be understood that the applied therapy may achieve the desired effect for the same disorder and/or may achieve different effects.

The compound or composition can be administered simultaneously with, before or after one or more additional pharmaceutical agents, which may be useful, for example, in complex therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and/or schedule determined for that pharmaceutical agent. Additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein, in a single dose, or administered separately in different doses. The specific combination for use in a treatment regimen will take into account the compatibility of the compound of the invention with 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 those used individually.

Examples of additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressants, and analgesic agents . Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in 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.

Pharmaceutical compositions of the present invention include compositions in which the active ingredient (eg, the compounds described herein, including variants or examples) is contained in a therapeutically effective amount, that is, in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, among other things, on the condition being treated. When administered in methods of 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 the target molecule (e.g., PTPN2 and/or PTPN1) and/or reducing, eliminating, or slowing the progression of the symptoms of the disease. Determining a therapeutically effective amount of a compound described herein is well within the ability of those skilled in the art, especially in light of the detailed description of the present invention.

The dosage and frequency (single or multiple doses) administered to a mammal may vary depending on a variety of factors, such as whether the mammal is suffering from another disease and its route of administration; size, age, sex, health, 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 concurrent treatment, complications from the disease being treated, or other health problems. Other therapeutic regimens or agents may be used in combination with the methods, compounds, and compositions described herein. Adjustment and manipulation of set dosages (eg, frequency and duration) is well within the reach of those skilled in the art.

For any compound described herein, a therapeutically effective amount may initially be determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of reaching the methods described here, as measured using the methods described here or known in the art.

As is well known in the art, therapeutically effective amounts for use in humans can also be determined in animal models. For example, a human dose may be formulated to achieve a concentration that has been found to be effective in animals. Dosage in humans can be adjusted by monitoring the effectiveness of the compounds and the dose is adjusted upwards or downwards as described above. Dose adjustment for maximum efficacy in humans based on the methods described above and other methods is well within the ability of the ordinary skilled person.

Dosages may vary depending on the requirements of the patient and the compound used. The dose administered to the patient, in the context of this invention, should be sufficient to influence a favorable therapeutic response in the patient over time. The size of the dose will also be determined by the presence, nature and extent of any adverse side effects. Determining the correct dosage for a particular situation is within the purview of the practitioner. Typically, treatment is started with smaller doses that are less than the optimum dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect under the circumstances is reached. Dosage sizes and intervals may be adjusted individually to provide levels of compound administered that are effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the person's disease condition.

Using the teachings herein, one can plan an effective prophylactic or therapeutic treatment regimen that does not cause significant toxicity and at the same time is effective in treating the clinical symptoms exhibited by a particular patient. This planning should include careful selection of the active compound by considering 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 chosen agent.

Also the object of the invention are kits ( for example , pharmaceutical packages). The kits provided herein may be useful in the prevention and/or treatment of a disease (eg, cancer, type 2 diabetes, obesity, metabolic disease, or other disease or condition described herein).

Presented kits may contain a pharmaceutical composition or compound according to the invention and a container (eg vial, ampoule, bottle, syringe and/or dispenser or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical diluent or suspension of a pharmaceutical composition or compound of the invention. In some embodiments, the proposed pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.

Thus, in one aspect, kits are provided that include a first container containing a compound described 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 include instructions for administering the described compound to a subject to prevent and/or treat the disease described herein.

Methods of treatment

The present disclosure provides compounds, compositions, and methods containing a compound described herein, for example, 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. Illustrative examples of diseases, disorders, or conditions include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic disease.

Oncological diseases

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is used to treat cancer. In the context of this document, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovaries, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, liver, including hepatocarcinoma, lymphoma, including B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphoma , Burkitt's lymphomas, small and large cells), 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, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, biliary tract cancer, adrenal cancer, salivary cancer cancer of the bronchus, cancer of the oral cavity, cancer of the oral cavity or pharynx, cancer of the larynx, cancer of the kidneys, gynecological cancer, cancer of the brain, cancer of the central nervous system, cancer of the peripheral nervous system, cancer of the hematological tissues, cancer of the small intestine or appendix, cervical cancer uterus, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer or carcinoma.

As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumors found in mammals, including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, B cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenström macroglobulinemia, benign monoclonal gammopathy , sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, stomach cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer glands (eg, ER positive, ER negative, chemotherapy resistance, Herceptin resistance, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobar carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer ( for example, hepatocellular carcinoma), lung cancer (for example, non -cell carcinoma of the lungs, plane cell carcinoma of the lungs, adenocarcinoma adenocolcinoma, lung -cell carcinoma of the lungs, fine cell carcinoma, sarcoma, sarcoma), multi -shaped neuroma, retinoblastoma, astrocyte, cranberries, cranes. OFARIGIOM, hemangoblastoy, Pinealom, ependymoma, oligodendroglioma, meningioma, glioma or melanoma. Additional examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung cancer, melanoma, mesothelioma, ovary, sarcoma, gastric, uterine, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, 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 of the endocrine or exocrine pancreas, medullary-type thyroid cancer, medullary thyroid carcinoma, melanoma , colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, breast nipple cancer, foliar cystosarcoma, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, fat storage cell carcinoma, or prostate cancer.

The term "leukemia" refers in general to progressive, malignant diseases of the hematopoietic organs and is usually characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is usually clinically 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) an increase or no increase in the number of abnormal cells in the blood: leukemic or aleukemic (subleukemic). Illustrative examples of leukemias that can be treated with a compound, pharmaceutical composition, or method provided herein include, for example, chronic leukemia, acute non-lymphocytic leukemia, acute lymphocytic leukemia, B-cell chronic lymphocytic 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, acute myelocytic leukemia, chronic myelocytic leukemia, cutaneous leukemia, fetal leukemia, eosinophilic leukemia, erythroleukemia, leukemia Gross, hairy cell leukemia, lymphoblastic leukemia, hemocytoblast leukemia, histiocytic leukemia, stem leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloid leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloblastic granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, Reader's cell leukemia, Schilling's leukemia, stem leukemia cells, subleukemic leukemia or undifferentiated cellular leukemia.

The term "sarcoma" usually refers to a tumor that is composed of a substance similar to embryonic connective tissue and usually consists of densely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that can be treated with a compound, pharmaceutical composition, or method provided herein include chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, malignant myxoma, osteosarcoma, Abemeti's sarcoma, malignant lipoma, liposarcoma, alveolar soft sarcoma tissue, ameloblast sarcoma, pampiniform sarcoma, chloroma, choriocarcinoma, embryonic sarcoma, Wilms tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblast sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma , B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, osteogenic sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous' sarcoma, serocystic sarcoma y, synovial sarcoma or telangiectal sarcoma.

The term "melanoma" refers to a tumor arising from the melanocytic system of the skin and other organs. Melanomas that can be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, epithelioid nevus, Clodmann's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, limited premalignant melanosis, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

The term "carcinoma" refers to a malignant neoplasm consisting of epithelial cells that tend to invade surrounding tissues and metastasize. Illustrative examples of carcinomas that can be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, breast carcinoma, Brenner carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma nomu, bronchiogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocellular carcinoma, chordoma, chorionic carcinoma, clear cell carcinoma, colloid carcinoma, colon carcinoma, comedonal carcinoma, body carcinoma, cribriform carcinoma, pleural carcinoma, skin carcinoma, columnar carcinoma, columnar cell carcinoma, cystadenocarcinoma , ductal carcinoma, ductal carcinoma, solid carcinoma, fetal carcinoma, encephaloid carcinoma, endometrioid carcinoma, epidermoid carcinoma, epithelial carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, carcinoma ex ulcere, fibrous carcinoma, gelatinous carcinoma, mucosal carcinoma, giant cell carcinoma Noma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonic carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Crompecher carcinoma, intraepithelial carcinoma , large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanotic carcinoma, breast carcinoma, mucinous carcinoma, muciparum carcinoma, mucocellular carcinoma, mucoep idermoid carcinoma, mucosal carcinoma, mucosal carcinoma, myxomatoid carcinoma, nasopharyngeal carcinoma, non-papillary renal cell carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, ovarian carcinoma, pancreatic duct carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, spiny cell carcinoma, purulent carcinoma, renal cell carcinoma kidney, reserve cell carcinoma, sarcoma-like carcinoma, Schneiderian carcinoma, squamous carcinoma, scrotum carcinoma, sebaceous carcinoma, seminoma, serous carcinoma, ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongiform carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, telangiectatic carcinoma, telangiectoid carcinoma, transitional cell carcinoma, tuberous carcinoma, tubular carcinoma, tuberous carcinoma, undifferentiated carcinoma, verrucous carcinoma, or carcinoma villosum.

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, some methods of treating cancer include reducing or reducing 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 the symptoms of cancer. In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), may be used as the sole agent in a composition or in combination with another agent in a composition for treating cancer, described herein (eg, pancreatic cancer, breast cancer, multiple myeloma, secretory cell cancer).

In some embodiments, compounds (compounds described herein, e.g., a compound of formula (I), formula (II), or formula (III)) and compositions (e.g., compositions containing a compound described herein, e.g., a compound Formulas (I), formulas (II), or formulas (III)) are used with cancer immunotherapy (e.g., checkpoint blocking antibody) to treat a subject (e.g., human), e.g., suffering from the disease or disorder described herein (e.g., , abnormal cell growth, such as cancer (eg, the cancer described herein)). The methods described herein include administering a compound described herein, such as a compound of formula (I), formula (II), or formula (III), and immunotherapy to a subject having abnormal cell growth, such as cancer. Illustrative examples of immunotherapy include but are not limited to the following:

In some embodiments, the immunotherapeutic agent is a compound (eg, ligand, antibody) that inhibits the immune checkpoint blockade pathway. In some embodiments, the immunotherapeutic agent is a compound that inhibits the indolamine-2,3-dioxygenase (IDO) pathway. In some embodiments, the immunotherapeutic agent is a compound that agonizes the STING pathway. Cancer immunotherapy refers to the use of the immune system to treat cancer. The three groups of immunotherapies used to treat cancer include cell-based, antibody, and cytokine-based therapies. All groups use cancer cells to display subtly different structures (eg, molecular structure; antigens, proteins, molecules, carbohydrates) on their surface that can be detected by the immune system. Cancer immunotherapy (e.g., antitumor immunotherapy or antitumor immunotherapies) 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 anti-cancer vaccines (eg, anti-tumor vaccines or neoantigen-based vaccines such as a peptide or RNA vaccine).

Cell therapy (eg, cancer vaccines) typically involves the removal of immune cells in a subject suffering from cancer, either from the blood or from a tumor. Tumor-specific immune cells will be activated, grow, and return to the cancer subject, where the immune cells provide an immune response against the cancer. Cell types that can be used in this way 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 for specific target antigens), TIL therapy (eg, injection of tumor infiltrating lymphocytes), TCR gene therapy, protein and nucleic acid vaccines. An illustrative example of cell therapy is Provenge. In some embodiments, the cell therapy is CAR-T therapy.

Interleukin-2 and interferon-alpha are examples of cytokines, proteins that regulate and coordinate the behavior of the immune system.

Cancer vaccines with neoantigens

Neoantigens are antigens encoded by tumor-specific mutated genes. Technological innovations have made it possible to analyze the immune response to patient-specific neoantigens resulting from tumor-specific mutations, and emerging evidence suggests that the recognition of such neoantigens is a major factor in the performance of clinical immunotherapy. 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 a cancer vaccine. These vaccines can be designed using peptides or RNA, such as synthetic peptides or synthetic RNA.

Antibody therapy is an antibody protein produced by the immune system that binds to a target antigen on the surface of a cell. Antibodies are usually encoded by the 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 able to specifically bind an antigen or epitope (Fundamental Immunology, ^3rd Edition, Paul, WE, ed., Raven Press, NY (1993). Specific binding occurs to the corresponding 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 higher than binding to irrelevant antigens The relative difference in affinity is often at least 25% greater, more often at least 50% greater more often at least 100% greater The relative difference can 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 times, for example.

Examples of antibody types include, without limitation, 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 a receptor from interacting with its ligand, or deliver the payload of chemotherapy or radiation, all of which can lead to cell death. Illustrative examples of antibodies for cancer treatment include, but are not limited to, alemtuzumab, bevacizumab, bretuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumumab, trastuzumab, nivolumab, pembrolizumab b, avelumab, durvalumab, and pidilizumab.

Blocking checkpoint antibodies

The methods described herein include, in some embodiments, the treatment of a human subject suffering from the disease or disorder described herein, comprising administering a composition comprising cancer immunotherapy (eg, an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a compound (eg, inhibitor or antibody) that inhibits the immune checkpoint blockade pathway. Immune checkpoint proteins under normal physiological conditions maintain self-tolerance (eg, prevent autoimmunity) and protect tissues from damage when the immune system responds to, for example, a pathogenic infection. Immune checkpoint proteins may not be regulated by tumors as an important immune resistance mechanism (Pardoll, Nature Rev. Cancer , 2012, 12, 252-264). Agonists of co-stimulatory receptors or antagonists of inhibitory signals (eg, immune checkpoint proteins) provide an increase in antigen-specific T-cell responses. Antibodies that block immune checkpoints do not directly target tumor cells, but usually target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

Exemplary checkpoint blocking antibodies include, but are not limited to, anti-CTLA-4, anti-PD-1, anti-LAG3 (eg, antibodies against lymphocyte activation gene 3), and anti-TIM3 (eg, antibodies against T- cell membrane protein 3). Illustrative examples of anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. Illustrative examples of anti-PD-1 ligands include, but are not limited to, PD-L1 (eg B7-H1 and CD274) and PD-L2 (eg B7-DC and CD273). Illustrative 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 . Illustrative examples of PD-L1-specific antibodies include, but are not limited to, BMS936559 (eg, MDX-1105), MEDI4736, and MPDL-3280A. Illustrative examples of checkpoint blocking antibodies also include, but are not limited to, IMP321 and MGA271.

T-regulatory cells ( eg CD4+, CD25+ or T-reg) are also involved in controlling the distinction between self and non-self (eg foreign) antigens and may represent an important mechanism for suppressing the immune response in many cancers. T-reg cells may arise from the thymus (eg, "natural T-reg") or may be produced by differentiation of mature T cells (eg, "induced T-reg"). Therefore, strategies that minimize the action of T-reg cells can be expected to promote the immune response to tumors.

IDO pathway inhibitors

The IDO pathway regulates the immune response by downregulating T-lymphocyte function and allowing local escape from the tumor. Expression of IDO by antigen-presenting cells (APCs) can lead to tryptophan depletion and, as a result, anergy of antigen-specific T cells and recruitment of 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 a cancer (eg, a tumor in a subject). Illustrative examples of inhibitors of the IDO pathway include indoxymod, epacadostat and EOS200271.

STING pathway agonists

Interferon gene stimulator (STING) is an adapter protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Evidence points to the involvement of the STING pathway in the induction of an antitumor immune response. For example, activation of the STING-dependent pathway in cancer cells can lead to tumor infiltration by immune cells and modulation of the anti-cancer immune response. STING agonists are being developed as a class of anticancer agents. Illustrative examples of STING agonists include MK-1454 and ADU-S100.

Costimulatory antibodies

The methods described herein include, in some embodiments, the treatment of a human subject suffering from the disease or disorder described herein, comprising administering a composition comprising cancer immunotherapy (eg, an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a co-stimulatory inhibitor or 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, as well as variants thereof.

The methods of the present invention involve single as well as multiple administration of a therapeutically effective amount of a compound as described herein. Connections, for example, the connection described in this document, you can enter at regular intervals depending on the nature, severity and extent of the condition of the subject. In some embodiments, the compound described herein is administered as a single dose. In some embodiments, the compound described herein is administered in multiple doses.

metabolic diseases

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 disorder. As used herein, the term "metabolic disease" refers to a disease or condition that affects the metabolic process in a subject. Illustrative examples of metabolic disorders 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 (eg, type I diabetes, type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

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 disorder (e.g., a metabolic disorder described herein) by reducing or elimination of the symptom of the disease. In some embodiments, the method of treatment includes reducing or eliminating a symptom including high blood pressure, high blood sugar, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like. In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), may be used as the sole agent in a composition or in combination with another agent in a composition to treat a metabolic disorder. substances.

Infectious diseases

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is used to treat an infectious disease. Illustrative examples of infectious diseases that can be treated with a compound described herein, such as a compound of formula (I), formula (II), or formula (III), include bacterial infections, viral infections (e.g., herpes, herpes zoster, influenza, colds, encephalitis) and parasitic infections.

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is used to treat an infectious disease (e.g., the infectious disease described herein) by reducing or eliminating a symptom diseases. In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), may be used as the sole agent in a composition or in combination with another agent in a composition for the treatment of an infectious disease. .

Parasitic infections

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is used to treat a parasitic infection.

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is used to treat a parasitic infection by reducing or eliminating a symptom of the disease. In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), may be used as the sole agent in a composition or in combination with another agent in a composition to treat a parasitic infection. .

Immunosuppressive diseases

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is used to treat an immunosuppressive disease.

In some embodiments, a compound described herein, such as a compound of formula (I), formula (II), or formula (III), is used to treat an immunosuppressive disease by reducing or eliminating a symptom of the disease. In some embodiments, a compound described herein, e.g., a compound of formula (I), formula (II), or formula (III), may be used as the sole agent in a composition or in combination with another agent in a composition for the treatment of an immunosuppressive disease. .

In some embodiments, the compounds described herein are provided as pharmaceutical compositions comprising the described compound, for example, formula (I), formula (II), or formula (III), and a pharmaceutically acceptable excipient. In embodiments of the method, the described compound, for example, formula (I), formula (II), or formula (III), is administered together with a second agent (eg, a therapeutic agent). In other embodiments of the method, the described compound, for example, formula (I), formula (II) or formula (III), is administered together with a second agent (eg, therapeutic agent), which is administered in a therapeutically effective amount.

Combination Therapy

Provided herein is a pharmaceutical composition comprising a compound as described herein, eg, a compound of formula (I), formula (II), or formula (III), as well as a second agent (eg, a second therapeutic agent). In some embodiments, the pharmaceutical composition includes a second agent (eg, a second therapeutic agent) in a therapeutically effective amount. In some embodiments, the second agent is an agent for treating cancer, a metabolic disease (eg, type 2 diabetes or obesity), or a disease or disorder that responds favorably to treatment with a PTPN2 or PTP1B inhibitor.

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 (eg, type 2 diabetes or obesity), or a disease or disorder that responds favorably to treatment. an inhibitor of PTPN2 or PTP1B, or with additional agents which may not be effective on their own but may contribute to the effectiveness of the active agent.

In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration includes administering two active agents at the same time, approximately simultaneously (eg, within about 1, 5, 10, 15, 20, or 30 minutes of each other) or sequentially in any order. In some embodiments, co-administration may be by co-formulation, that is, by the preparation of a single pharmaceutical composition comprising both active agents. In other embodiments, active agents may be prepared separately. In another embodiment, the active and/or auxiliary agents may be linked or conjugated to each other. In some embodiments, the compounds described herein can be combined with the treatment of cancer, a metabolic disease (eg, type 2 diabetes or obesity), or a disease or disorder that responds favorably to treatment with PTPN2 or PTP1B inhibitors. In embodiments of the invention, the second agent is an anticancer agent. In embodiments of the invention, the second agent is a chemotherapeutic drug. In embodiments of the invention, the second agent is an agent for the treatment of a metabolic disease. In embodiments of the invention, the second agent is an anti-diabetic agent. In some embodiments, the second agent is an anti-obesity agent.

Anticancer agents

"Anticancer agent" is used in accordance with its usual meaning and refers to a composition (eg, compound, drug, antagonist, inhibitor, modulator) that has antineoplastic properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anticancer agent is a chemotherapeutic agent. In some embodiments, the anticancer agent is an agent identified herein useful for use in methods of treating cancer. In some embodiments of the invention, the anticancer agent is an agent approved by the US FDA or similar regulatory authority in another country for the treatment of cancer. Examples of anticancer agents include, but are not limited to, MEK inhibitors (e.g., MEK1, MEK2, or MEK1 and MEK2) (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), alkylsulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomustine, semustine, streptozocin), triazenes (e.g. decarbazine), antimetabolites (e.g. , 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (eg, methotrexate) or pyrimidine analogs (eg, fluorouracil, eg, floxuridine, cytarabine), purine analogs (eg, mercaptopurine, thioguanine, pentostatin ), etc.), plant alkaloids (e.g. vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisometerase inhibitors (e.g. irinotecan, topotecan, amsacrine, etoposide (VP 16) , etoposide phosphate, teniposide, etc.), anticancer antibiotics (e.g. doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxanthamycin, etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (eg, mitoxantrone), substituted urea (eg, hydroxyurea), methylhydrazine derivative (eg, procarbazine), adrenal suppressant (eg, mitotane, aminoglutethimide (aminoglutethimide), 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, inhibitors Syk, mTOR inhibitors, antibodies (eg, rituxan), gossyfol, genasens, polyphenol E, chlorfusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL), 5-aza- 2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.R™.), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), LY294002, bortezomib, trastuzumab , BAY 1 1-7082, PKC412, PD184352, 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adcipenol; adoselezin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; irografolide; angiogenesis inhibitors; antagonist D; G antagonist; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen, prostate carcinomas; antiestrogen; antineoplaston; antisense oligonucleotides; aficoline glycinate; apoptosis gene modulators; apoptosis regulators; apuric acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrin; atamestan; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; Azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorines; benzoyl-staurosporine; derivatives of beta-lactam; beta-alethine; beta-amycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafid; bistratene A; bizelesin; breflat; bropyrimine; budotitan; butionine sulfoximine; calcipotriol; calphostin C; derivatives of camptothecin; IL-2 canarypox; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; Carest M3; CARN 700; inhibitor of cartilage origin; 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; analogue of combretastatin; conagenin; crambecidine 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodydemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquon; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron; doxyfluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosin; edrecolomab; eflornithine; element; emitfur; epirubicin; episteride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastin; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimeks; formestane; fostriecine; fotemustine; gadolinium texafirin; gallium nitrate; halocytabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; idramantone; ylmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; an insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplakt; irsogladin; isobengazole; isogomochalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leunamycin; lenograstim; lentinan sulfate; leptostatin; letrozole; leukemia inhibitory factor; leukocyte alpha-interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozol; analogue of linear polyamine; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribin; lurtothecan; lutetium texafirin; lysophyllin; lytic peptides; maytansine; manostatin A; marimastat; mazoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaryl; merbaron; metererin; methioninase; metoclopramide; an MIF inhibitor; mifepristone; miltefosine; peaceful; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafid; mitotoxin, fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramming; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A+myobacteria cell wall sk; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor 1 therapy; anti-cancer mustard; micaperoxide B; extract of the cell wall of mycobacteria; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; pile; naloxone + pentazocine; napavin; nafterpine; nartograstim; nedaplatin; nemorubicin; non-ridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrulline; 06-benzylguanine; octreotide; okicenon; oligonucleotides; onapriston; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osateron; oxaliplatin; oxaunomycin; palauamine; palmitoyl rhizoxin; pamidronic acid; panoxytriol; panomifen; parabactin; paselliptin; pegaspargase; peldesin; pentosan polysulfate sodium; pentostatin; pentrosol; perflubron; perphosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pyrarubicin; pyritrekim; placetin A; placetin B; a plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; sodium porfimer; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A immunomodulator; a protein kinase C inhibitor; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; conjugate of pyridoxylated hemoglobin with polyoxyethylene; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptin demethylated; rhenium etidronate Re 186; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukin; romurtide; rockwinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; aging inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transmission modulators; single chain antigen binding protein; sizofuran; sobuzoxan; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparphonic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stypiamide; stromelysin inhibitors; sulfinosine; superactive antagonist of vasoactive intestinal peptides; suradista; suramin; swainsonine; synthetic glycosaminoglycans; thallimustin; tamoxifen metiodide; tavromustine; tazarotene; sodium tecogalan; tegafur; tellurapyrylium; telomerase inhibitors; temporfin; temozolomide; teniposide; tetrachlorodecoxide; tetrazomin; taliblastin; thiocoralin; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid-stimulating hormone; tin ethyl etiopurpurine; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; genitourinary sinus growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velarezole; veramin; verdun; verteporfin; vinorelbine; vinxaltin; vitaxin; vorozol; zanoterone; zeniplatin; zilascor; cynostatin stimalamer, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; adoselezin; aldesleukin; altretamine; ambomycin; amethantron acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brekvinar sodium; bropyrimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; cristnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; desaguanine; desaguanine mesylate; diaziquon; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromat; epipropidin; epirubicin hydrochloride; erbulozol; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozol hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocytabine; fosquidon; fostriecine sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimophosine; interleukin II (including recombinant interleukin II or rIL 2), interferon alfa-2a; interferon alfa-2b; interferon alpha-nl; interferon alpha-n3; interferon beta-la; interferon gamma-lb; iprop latin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; mazoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaryl; mercaptopurine; methotrexate; sodium methotrexate; methoprine; meturedepu; mitindomide; mitocarcin; mitocromine; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perphosphamide; pipobroman; piposulfan; pyroxantrone hydrochloride; plicamycin; plomestan; sodium porfimer; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; rogletimide; safingol; safingol hydrochloride; semustine; symtrazen; sodium sparphosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; tegafur; teloxantrone hydrochloride; temporfin; teniposide; teroxirone; testolactone; thiamiprin; thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulosole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; winepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozol; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in G2-M phases and/or modulate microtubule formation or stability (eg, taxol, i.e., paclitaxel), taxotere, taxane skeletal compounds, erbulosol (i.e., R-55104 ), dolastatin 10 (i.e., DLS-10 and NSC-376128), mivobulin isethionate (i.e., CI-980), vincristine, NSC-639829, discodermolide (i.e., NVP-XX-A-296 ), ABT-751 (Abbott, i.e. E-7010 ), altorgirtins (i.e., altorhirtin A and altorgirtin C), spongistatins (i.e., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5 , spongistatin 6, spongistatin 7, spongistatin 8 and spongistatin 9), cemadotin hydrochloride (i.e. LU-103793 and SC-D-669356), epothilones (i.e. epothilone A, epothilone B, epothilone C (i.e. deoxyepothilone A or dEpoA), epothilone D (i.e. KOS-862, dEpoB and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-azaepothilone B, 21-aminoepothilone B ( i.e. BMS-310705), 21-hydroxyepothilone D (i.e. e. deoxyepothilone F and dEpoF), 26-fepotilone, 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 of 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), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e. AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, t e. AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), vitilevuamide, tubulizin A, canadiensole, centaureidine (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 (Kansas State University), H16 (Kansas State University ), oncocidin A 1 (i.e. e. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Figianolide 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), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3 -BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-191), ™PN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), monsatrol, inanocin (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 desmethyleleuterobine, desethyleleuterobine, isoeleutherobin A and Z-eleutherobin), caribaeoside, caribaeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), tassalonolid A , TUB-245 (Aventis), A-259754 (Abbott), diosostatin, (-)-phenylahistin (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. SPA110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D- 82318 (Zentaris), SC-12983 (NCI), sodium resverastatin phosphate, BPR-OY-007 (National Health Research Institutes) and SSR-25041 1 (Sanofi), steroids (eg, dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (eg prednisone), progestins (eg hydroxyprogesterone caproate, megestroal acetate, medroxyprogesterone acetate), estrogens (eg diethylstilbestrol, ethinylestradiol), antiestrogen (eg tamoxifen), androgens (eg , testosterone propionate, fluoxymesterone), antiandrogen (eg, flutamide), immunostimulants (eg, Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, interferon alpha, etc.), monoclonal antibodies (eg, anti-CD20 , anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-Calichemycin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc. ), radioimmunotherapy (eg, anti-CD20 monoclonal antibody conjugated to ^m ln, ⁹⁰ Y, or ¹³¹ I, etc.), triptolide, homogarringtonin, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, serivastatin, vincristine, deoxyadenosine , sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefinitib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic agent (eg, gefinitib (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), but not limited to sorafenib, imatinib, sunitinib, dasatinib or the like.

"Chemotherapeutic agent" or "chemotherapeutic agent" is used in accordance with their usual meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit cell growth or proliferation.

In addition, the compounds described herein may be co-administered with conventional immunotherapeutic agents, including immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, interferon alpha, etc.), monoclonal antibodies ( e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicimycin conjugate, anti-CD22 monoclonal antibody conjugate of Pseudomonas aeruginosa exotoxin etc.) and radioimmunotherapy (eg, anti-CD20 monoclonal antibody conjugated with ^m In, ⁹⁰ Y or ¹³¹ I, etc.), but not limited to.

In another embodiment, the compounds described herein may be co-administered with conventional radiotherapeutic agents, including 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 with, but not limited to, antibodies directed against tumor antigens.

EXAMPLES

The following examples are provided for a more complete understanding of the invention described herein. The synthesis examples and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods proposed herein, and should in no way be construed as limiting their scope.

Synthesis protocols

Compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below, which are well known to those skilled in the art. It is understood that where typical or preferred process conditions (i.e., reaction temperature, time, mole ratios of reactants, solvents, pressures, etc.) are indicated, other process conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary with particular reactants or solvents, but such conditions can be determined by those skilled in the art using routine optimization procedures. The general scheme relating to processes for the preparation of exemplary compounds of the invention is further described in the "Processes for the preparation of exemplary compounds" section.

In addition, as will be appreciated by those skilled in the art, conventional protecting groups may be needed to prevent undesired reactions of certain functional groups. The selection of an appropriate 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 and their introduction and removal are described in Greene et al ., Protecting Groups in Organic Synthesis , Second Edition, Wiley, New York, 1991 and references cited there.

Abbreviations

CIAD - atmospheric pressure chemical ionization; CID - chemical ionization desorption; DMSO - dimethyl sulfoxide; ESI - electrospray ionization; HPLC - high performance liquid chromatography; LC/MS - liquid chromatography/mass spectrometry; LED - LED; MS - mass spectrometry; NMR - nuclear magnetic resonance; psi inch - pounds per square inch; and TLC - thin layer chromatography.

Example 1: 5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione (Compound 100)

Example 1A: Benzyl 3-(benzyloxy)-7-bromonaphthalene-2-carboxylate

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 minutes at 23°C . Thereafter, benzyl bromide (89.0 mL, 749 mmol) was added and the internal temperature raised to 49°C. After 90 minutes 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 H ₂ O (3×1 L) and tert -butyl methyl ether/heptanes (1:2, 2×300 ml) and then dried in vacuum (15 mbar) at 45°C to constant weight to obtain the title compound (160.3 g, 358 mmol, 96% yield) as an off-white solid. MS (CIAD ⁺ ) m/z 449 [M+H] ⁺ .

Example 1B: 3-(benzyloxy)-7-bromonaphthalene-2-carboxylic acid

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 agitated by mechanical stirring from above and heated to an internal temperature of 70°C. After 3 hours, the mixture was cooled to room temperature in an ice bath and 6 M HCl (168 ml) was added over 5 minutes, which resulted in the precipitation of an off-white solid. The solid was collected by filtration and washed with H ₂ O (2 x 1 L), triturated with t -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

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 atmosphere, and diphenyl phosphorazidate (64.4 ml, 300 mmol) was added dropwise over 90 minutes with the entire reaction behind a reflective screen. After 5 hours the reaction mixture was cooled to room temperature, diluted with H ₂ O (1.5 L) and extracted with ethyl acetate (2×400 ml). The combined organic layers were washed with brine (2×150 ml), dried over sodium sulfate, filtered and concentrated to give a white solid. The solid was taken to the hydrolysis step without further purification.

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, during which time a homogeneous dark orange solution was formed. After 13 hours the mixture was cooled to room temperature in an ice bath and slowly added H ₂ O (800 ml) over 3 minutes, which led to the precipitation of a yellow solid and a simultaneous exothermic transition 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 back extracted with CH ₂ Cl ₂ (3×150 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 under vacuum (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 (CIAD+) m/z 329 [M+H] ⁺

Example 1D: methyl {[3-(benzyloxy)-7-bromonaphthalen-2-yl]amino}acetate

_Methyl 2 -bromoacetate (29.3 ml, 310 mmol). The suspension was vigorously stirred at room temperature for 5 minutes, then heated to an internal temperature of 60°C. After 4 hours 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 in vacuo (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-fluoronaphthalen-2-yl]amino}acetate

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) for 5 minutes. The resulting solution was stirred for 15 minutes 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 minutes at room temperature. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×75 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 seconds. Heptanes (150 ml) were then slowly added via addition funnel over 15 minutes. The resulting yellow solid was collected by filtration and washed with 33% v/v. ethyl acetate in heptanes (3 × 60 ml). The solid was decanted 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 minutes, after which it was 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 , yield 64.7%) 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](sulfamoyl)amino}acetate

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 keep the internal temperature below 10°C. C. After stirring for 30 minutes at 0°C, a 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 through addition funnel so that the internal temperature remains below 10°C. After the addition was completed, the addition funnel was washed with dichloromethane (12.5 ml). The resulting solution was stirred for 30 minutes at 0°C and then left to cool to room temperature. After 1 hour the reaction mixture was quenched with H ₂ O (73 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2×36 ml). The combined organic layers were washed with 1 M sodium bisulfate (2×73 ml). The aqueous wash material was back-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 which was used without purification. MS (APCI ⁺ ) m/z 541, 543 [M- tert -butyl+H] ⁺ .

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 minutes, the reaction was quenched by slow addition of saturated aqueous sodium bicarbonate (230 ml) via 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 an orange foam which was suspended in dichloromethane (20 ml) and stirred for 5 minutes to give a suspension which was diluted by adding heptanes (40 ml) dropwise via an addition funnel. The resulting yellow solid was collected by filtration, washed with 25% v/v. 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-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A solution of sodium methoxide (16.65 ml, 72.8 mmol) (25 wt.% in methanol) and the resulting solution at room temperature. After 20 minutes 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 4:1 with 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 up to 40 ml total volume. The resulting yellow suspension was diluted with dichloromethane (72 ml) then slowly diluted with heptanes (72 ml). The suspension was sonicated for 30 seconds and stirred for 5 minutes at room temperature. The resulting white solid was collected by filtration, then washed with 25% v/v. dichloromethane in heptanes (72 ml) and dried in vacuo (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- d ₆ ) 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 (ESI ^- ) m/z 463, 465 [MH] ^- .

Example 1H: 5-[3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, ammonium salt

In a 500 ml round bottom flask, the product of example 1G (9 g, 19.34 mmol), RockPhos Pd G3 precatalyst (0.324 g, 0.387 mmol) and cesium carbonate (18.9 g, 58.0 mmol) were combined. The solids were placed under vacuum and stirred for 5 minutes, then the flask was filled with nitrogen and the prepared mixture of N,N -dimethylformamide (90 ml) and H ₂ O (1.045 ml, 58.0 mmol) was added. The resulting slurry was degassed with five vacuum/nitrogen backfill cycles and then heated to an internal temperature of 80°C. After 3 hours the reaction mixture was cooled to room temperature, quenched by 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 (2×50 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (4×50 ml). The combined aqueous washing material was back-extracted with ethyl acetate (3×50 ml). The combined organics 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 addition funnel over 5 minutes with vigorous stirring. The resulting black solid was removed by filtration and washed with 50% v/v. tert -butyl methyl ester in ethyl acetate (2 x 45 ml). The solid was decanted and the filtrate was concentrated in vacuo. The resulting dark oil was diluted with methanol (9 ml) and then a solution of ammonia in methanol (2.76 ml, 7 M, 19.34 mmol) was added. The resulting solution was diluted by slow addition of 50% vol./about. ethyl acetate in heptanes (135 ml) via addition funnel. The resulting solid was collected by filtration, then washed with cold filtrate, then 50% v/v. ethyl acetate in heptanes (45 ml) and dried in vacuo (15 mbar) at 50° C. to constant weight to give the title compound as the 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 (ESI ^- ) m/z 401 [MH] ^- .

Example 1I: 5-{3-(benzyloxy)-1-fluoro-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A mixture of 2-morpholinoethanol (1.69 g, 12.9 mmol), triethylamine (2.70 ml, 19.35 mmol) and anhydrous dichloromethane (71.7 ml) was cooled to 0°C. Thereafter, methanesulfonyl chloride (1.206 ml, 15.48 mmol) was added dropwise over 5 minutes, after 10 minutes the reaction mixture was warmed to room temperature and stirred for another 30 minutes. Most of the dichloromethane was removed in vacuo and the resulting residue was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (2×30 ml), dried over sodium sulfate, filtered and devolatilized in vacuo at 29°C to give 2 -morpholinoethyl methanesulfonate (1.71 g, 8.17 mmol, 63.3% yield) as an amorphous yellow residue, which was used directly in the next reaction.

Cesium carbonate (186 mg, 0.572 mmol) was added to a solution of the product of example 1H (120 mg, 0.286 mmol) in N,N -dimethylformamide (954 μl). The suspension was stirred at room temperature for 5 minutes followed by the addition of 2-morpholinoethyl methanesulfonate (114 mg, 0.544 mmol). The reaction was heated to 40°C. After 80 minutes the mixture was cooled to room temperature. The residual cesium carbonate was collected by filtration and washed with cesium carbonate dimethyl sulfoxide (1×500 µl) to give a dark yellow filtrate containing crude product, which was purified by HPLC (Phenomenex® Luna® 10 µM C18(2) 100 Å, AXIA™ column (00G-4253-U0-AX), 250 x 300 mm, flow rate 50 ml/minute, 5-95% acetonitrile gradient in buffer (0.025 M aqueous ammonium acetate) to give the title compound (75.5 mg, 0.146 mmol, yield 51%) MS (APCI ⁺ ) m/z 516 [M+H] ⁺ .

Example 1J: 5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione hydrochloride

A mixture of the product of Example 1I (68.2 mg, 0.132 mmol) and pentamethylbenzene (58.8 mg, 0.397 mmol) in dichloromethane (661 μl) was cooled to an internal temperature of -76° C. under dry nitrogen. Thereafter, a 1 M solution of boron trichloride (1.59 ml, 1.59 mmol) in CH ₂ Cl ₂ was added dropwise over 15 minutes so as not to raise the internal temperature more than -72°C. The reaction was heated to 0°C and stirred for 20 minutes. After that, the mixture was re-cooled to -76°C and quickly extinguished with anhydrous methanol (2.67 ml, 66.1 mmol). The resulting colorless homogeneous solution was heated to room temperature for 20 minutes under nitrogen. Volatiles were removed in vacuo to give an off-white solid which was purified by HPLC (Phenomenex® Luna® 10 μM C18(2) 100 Å column, AXIA™ (00G-4253-U0-AX), 250 x 300 mm, flow rate 50 ml/minute, 5-95% gradient of acetonitrile in buffer (0.025 M aqueous ammonium acetate) to give the title compound as the ammonium salt EE was suspended in methanol/ethyl acetate (1:1, 2 ml) and treated with freshly prepared 1 M solution of anhydrous hydrochloric acid in ethyl acetate (66 μl, 0.066 mmol) After stirring for 5 minutes at room temperature, the volatiles were removed in vacuo (15 mbar) and the resulting white solid was dried at 35°C to give the indicated in title compound (22.6 mg, 0.053 mmol, 40% yield) ¹ H NMR (DMSO- d ₆ ) δ ppm 9.89 (br s, 1H), 9.57 (s, 1H) , 7.73 (dd, J=9.1, 1.1 Hz, 1H), 7.30 (d, J=2.5 Hz, 1 H), 7.21 (dd, J=9.1, 2.5Hz, 1H), 7.06(s, 1H), 4.47(t, J=4.8Hz, 2H), 4.11(s, 2H), 3.84(m, 4H ), 3.59 (s, 2H), 3.34 (m, 2H); MS (APCI ⁺ ) m/z 426 [M+H] ⁺ .

Example 2: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trione (Compound 101)

Example 2A: tert-butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] pyrrolidine-1-carboxylate

The product from Example 14A (340 mg, 0.614 mmol) and tetrahydrofuran (THF) (1 mL) were added to 5% wet Pt/C (100 mg, 0.211 mmol) in a 20 mL Barnstead Hastelloy C reactor and stirred for 0.55 h at 50 psi inch of hydrogen at 25°C. The reaction mixture was filtered, the volatiles were removed under reduced pressure, and the crude residue was subjected to column chromatography (SiO ₂ , dry load with diatomaceous earth, 5% methanol in dichloromethane) to give the title compound (164 mg, 0.295 mmol, 48% yield) as white solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.82-7.69 (m, 2H), 7.59-7.52 (m, 2H), 7.54-7.47 (m, 1H), 7.40-7.33 (m, 2H), 7.36-7.27 (m, 2H), 5.25 (s, 2H), 4.08 (s, 2H), 3.76 (dd, J=10.4, 7.5 Hz, 1H), 3.59-3.45 (m, 2H), 3.33-3.23 (m, 2H), 3.17 ( s, 1H), 2.26 (s, 1H), 2.04 (q, J=9.9 Hz, 1H), 1.43 (d, J=5.9 Hz, 9H); MS (CIAD ^- ) m/z 554 [MH] ^- .

Example 2B: 5-[3-(benzyloxy)-1-fluoro-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A solution of the product of example 2A (164 mg, 0.295 mmol) and trifluoroacetic acid (1 ml, 12.98 mmol) in dichloromethane (2 ml) was stirred at room temperature for 1 hour. Volatiles were removed under reduced pressure. Dichloromethane (5 ml) was added and the volatiles were again removed under reduced pressure. The residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (77 mg, 0.169 mmol, 57% yield) as a white solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 8.77 (s, 2H), 7.87-7.79 (m, 2H), 7.57-7.43 (m, 3H ), 7.42-7.25 (m, 5H), 5.24 (s, 2H), 4.07 (s, 2H), 3.70-3.57 (m, 2H), 3.18 ( dd, J=10.9, 9.3 Hz, 1H), 2.41 (dtd, J=13.0, 7.1, 3.5 Hz, 1H), 2.02 (dc, J=12, 6, 9.5 Hz, 1H); MS (CIAD-) m/z 454 [MH] ^- .

Example 2C: 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5 ^- thiadiazolidin-1,1, 3-trione

To a solution of the product of example 2B (77 mg, 0.169 mmol) in dichloromethane (5 ml) was added cyclopropanesulfonyl chloride (0.041 ml, 0.338 mmol) at room temperature, followed by N -ethyl- N -isopropylpropan-2-amine (0.089 ml , 0.507 mmol). The reaction was stirred overnight at room temperature. Additional N -ethyl- N -isopropylpropan-2-amine (0.089 mL, 0.507 mmol) was added resulting in a clear solution. After 3 hours stirring at room temperature, the volatiles were removed under reduced pressure and the crude was subjected to column chromatography (SiO ₂ , dry load diatomaceous earth, 8% CH ₃ OH in CH ₂ Cl ₂ ) to give the title compound (80 mg, 0.143 mmol , 85% yield. MS (CIAD-) m/z 558 [MH] ^- .

Example 2D: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trion

The product from example 2C (80 mg, 0.143 mmol) and 1,2,3,4,5-pentamethylbenzene (63.6 mg, 0.429 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (5 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.429 ml, 0.429 mmol) in dichloromethane was added dropwise over 5 minutes. After 20 minutes, the reaction was quenched at -78°C with dichloromethane:ethanol=9:1 (1 ml), and then slowly warmed to room temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [column Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ (250 mm × 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (36 mg, 0.077 mmol, 54% yield) . ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.74 (s, 1H), 7.70 (t, J=1.2 Hz, 1H), 7.66 (dd, J= 8.8, 1.5 Hz, 1H), 7.41 (dd, J=8.7, 1.8 Hz, 1H), 6.99 (s, 1H), 4.05 (s, 2H), 3.74 (dd, J=9.7, 7.6 Hz, 1H), 3.60-3.46 (m, 2H), 3.42-3.36 (m, 1H), 3.30 - 3.26 (m, 1H), 3.27-3.17 (m, 1H), 2.77-2.68 (m, 1H), 2.03 (dc, J=12.0, 9.0 Hz, 1H), 0.98-0.85 (m, 4H); MS (CIAD-) m/z 467 [MH] ^- .

Example 3: 5-[1-Fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 102 )

Example 3A: tert-Butyl 3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidin- 1-carboxylate

The product from Example 14A (300 mg, 0.560 mmol) in tetrahydrofuran (THF) (5 ml) was added to 5% wet Pd/C (500 mg, 2.189 mmol) in a 20 ml Barnstead Hastelloy C reactor and the mixture was stirred for 6 hours at 50 psi inch of hydrogen at 25°C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was used in the next step without further purification. MS (CIAD-) m/z 446 [MH] ^- .

Example 3B: 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the product of example 3A (20 mg, 0.043 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml, 12.98 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (7 mg, 0.019 mmol, 27% yield) as a white solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.73 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.42-7.36 ( m, 1H), 7.00 (s, 1H), 4.03 (s, 2H), 3.62-3.51 (m, 2H), 3.23-3.13 (m, 2H), 3 .13-3.05 (m, 1H), 2.34 (ddd, J=12.7, 6.7, 3.5 Hz, 1H), 1.95 (dc, J=12.7, 9, 4 Hz, 1H); MS (CIAD-) m/z 363 [MH] ^- .

Example 4 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl propan-2-ylcarbamate (Compound 103)

Example 4A: 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl propan-2-ylcarbamate

To a solution of the product of example 1H (80 mg, 0.199 mmol) in N,N -dimethylformamide (1 mL) was added 4-dimethylaminopyridine (4.86 mg, 0.040 mmol) and isopropyl isocyanate (22.00 mg, 0.258 mmol). The mixture was stirred at ambient temperature for 14 hours. After that, the reaction mixture was filtered, purified by preparative HPLC on a Phenomenex® Luna® 10 μm C18 column (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) with 0.1 % trifluoroacetic acid at a flow rate of 50 ml/minute (0-1 min 10% A, 1-20 linear gradient 10-100%) to give the title compound (48 mg, 0.098 mmol, 49.5% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.93 (d, J=8.9 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7 .78 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.56-7.50 (m, 2H), 7.44-7.30 (m, 5H), 5.27 (s, 2H), 4.42 (s, 2H), 3.73-3.66 (m, 1H), 1.16 (d, J=6.6 Hz, 6H); MS (CIAD ^- ) m/z 486 [MH] ⁺ .

Example 4B: 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl propan-2-ylcarbamate

To a mixture of the product of Example 4A (42 mg, 0.086 mmol) and pentamethylbenzene (63.9 mg, 0.431 mmol) in dichloromethane (2 mL), cooled to -78°C, was added dropwise a solution of boron trichloride (1 M, 0.517 mL, 0.517 mmol) in dichloromethane for 5 minutes. After 30 minutes the reaction was quenched with 2 N HCl (0.5 ml). The reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC using a Phenomenex® Luna® 10 µm C18 column (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) with 0.1% trifluoroacetic acid at a flow rate of 50 ml/minute (0-1 min 10% A, 1-20 min linear gradient 10-70%) to give the title compound (28 mg, 0.070 mmol, 82% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.59 (s, 1H), 7.78 (dd, J=11.2, 8.3 Hz, 2H), 7.55 ( d, J=2.3 Hz, 1H), 7.29 (dd, J=8.9, 2.3 Hz, 1H), 7.14 (s, 1H), 4.48 (s, 2H), 3.73-3.65 (m, 1H), 1.15 (d, J=6.6 Hz, 6H); MS (CIAD ^- ) m/z 396 [MH] ⁺ .

Example 5 5-(9-fluoro-7-hydroxynaphtho[2,1- b ]furan-8-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 104)

Example 5A: 5-[3-(benzyloxy)-7-(2,2-dimethoxyethoxy)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the product of Example 1H (500 mg, 1.243 mmol) and cesium carbonate (891 mg, 2.73 mmol) in N,N -dimethylformamide (5 mL) was added 2-bromo-1,1-dimethoxyethane (420 mg, 2.485 mmol ). The reaction was stirred at 75°C for 5 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the residue was subjected to column chromatography (SiO ₂ , dry load diatomaceous earth, 15% CH ₃ OH in CH ₂ Cl ₂ ) to give the title compound (475 mg, 0.968 mmol, yield 78%) as a beige solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.76 (dd, J=9.1, 1.4 Hz, 1H), 7.56 (dt, J=6.6, 1 .4 Hz, 2H), 7.40-7.32 (m, 2H), 7.34-7.26 (m, 3H), 7.22 (dd, J=9.0, 2.6 Hz, 1H), 5.22 (s, 2H), 4.75 (t, J=5.1 Hz, 1H), 4.11 (d, J=5.1 Hz, 2H), 4.09 (s, 2H), 3.38 (s, 6H); MS (CIAD-) m/z 489 [MH] ^- .

Example 5B: 5-[7-(2,2-dimethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3-trione

The product from Example 5A (475 mg, 0.968 mmol) in tetrahydrofuran (THF) (10 ml) was added to 5% wet Pd/C (475 mg, 2.080 mmol) in a 20 ml Barnstead Hastelloy C reactor and stirred for 15 minutes under conditions 50 psi inch of hydrogen at 25°C. The mixture was filtered and the crude material was subjected to column chromatography (SiO ₂ dry load diatomaceous earth, 15% CH ₃ OH in CH ₂ Cl ₂ ) to give the title compound (182 mg, 0.455 mmol, 47% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.50 (s, 1H), 7.68 (dd, J=9.1, 1.4 Hz, 1H), 7.21 ( d, J=2.6 Hz, 1H), 7.16 (dd, J=9.0, 2.6 Hz, 1H), 7.03 (s, 1H), 4.74 (t, J=5 .1 Hz, 1H), 4.09 (d, J=4.9 Hz, 4H), 3.37 (s, 6H); MS (CIAD-) m/z 398 [MH] ^- .

Example 5C: 5-(9-fluoro-7-hydroxynaphtho[2,1-b]furan-8-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A solution of the product of example 5B (30 mg, 0.075 mmol) and trifluoroacetic acid (1 ml, 12.98 mmol) in dichloromethane (2 ml) was stirred at room temperature for 1 hour. Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (12 mg, 0.036 mmol, 48% yield) as a beige solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 8.13 (d, J=2.0 Hz, 1H), 7.96 (s, 3H), 7.77 (d, J= 8.9 Hz, 1H), 7.66 (dd, J=9.0, 1.7 Hz, 1H), 7.33 (dd, J=3.8, 2.0 Hz, 1H), 7, 23 (d, J=1.3 Hz, 1H), 4.13 (s, 2H); MS (CIAD-) m/z 334 [MH] ^- .

Example 6: 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trione (Compound 105)

Example 6A: 5-{7-[2-(azetidin-1-yl)ethoxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin- ^1,1 , 3-trione

Mixture of the product of Example 1H (121 mg, 0.3 mmol), 1-(2-chloroethyl)azetidine, hydrochloric acid (94 mg, 0.600 mmol), cesium carbonate (391 mg, 1.20 mmol), and triethylamine (100 mg, 0.990 mmol) in dimethylformamide (0.8 ml) was stirred at 70° C. for 1.5 hours. The solution was filtered and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with dichloromethane followed by dichloromethane/methanol (7:1) to give the title compound (35 mg, 0.072 mmol, 24% yield) as a solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.80 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz, 2H), 7.37 (t , J=8 Hz, 2H), 7.31 (m, 3H), 7.23 (dd, J=8, 2 Hz, 1H), 5.23 (s, 2H), 4.28 (t, J =8 Hz, 2H), 4.09 (s, 2H), 4.01 (t, J=8 Hz, 4H), 2.31 (m, 2H); MS (ESI ^- ) m/z 484 [MH] ^- .

Example 6B: 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trion

Trichloroborane (0.700 ml, 0.700 mmol, 1.0 M in dichloromethane). The mixture was stirred at -78°C for 40 minutes. At -78°C was added methanol (3 ml). The mixture was stirred for 5 minutes at room temperature and then concentrated under reduced pressure. The resulting solids were washed with heptane (5 ml×4), then dissolved in methanol (0.5 ml) and N,N -dimethylformamide (3 ml). This material was purified by preparative HPLC [YMC TriArt™ C18 hybrid 20 µm column, 25×150 mm, flow rate 80 ml/min, 5-100% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide )] to give the title compound (20 mg, 0.051 mmol, 72% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.54 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.25 (d, J=2 Hz , 1H), 7.17 (dd, J=8, 2 Hz, 1H), 7.05 (br s, 1H), 4.28 (t, J=8 Hz, 2H), 4.09 (s , 2H), 4.08 (t, J=8 Hz, 4H), 2.33 (m, 2H); MS (ESI ^- ) m/z 394 [MH] ^- .

Example 7 5-[1-Fluoro-3- _hydroxy -7-methoxy(4-2H ⁾ naphthalen-2-yl](4,4-2H ² ) -1 λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione (Compound 106)

Sodium hydride (0.061 g , 1.532 mmol _, 60% in mineral oil). All solids went into solution, after which the mixture was heated to 60°C. After 72 hours, deuterium enrichment was complete as indicated by ¹ H NMR. The volatiles were removed and the solution was treated with DCl in D ₂ O (1.839 ml, 1.839 mmol, 1 N solution) and ethyl acetate (3 ml). The layers were shaken in a tube and separated, and the organic layer was concentrated under reduced pressure. The resulting organic residue was partitioned between a layer of dimethyl sulfoxide:methanol (2 ml 1:1) and a layer of heptane (1 ml) to remove any mineral oil before purification. Layer separation and purification of the DMSO:methanol layer by reverse phase HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (150 mm × 30 mm); A 3-100% gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) over 17 minutes at a flow rate of 50 ml/minute] gave a white solid which was dissolved in D ₂ O:CH ₃ CN (2 ml, 1:1). The solution was frozen with dry ice and lyophilized to give the title compound as a light white powder (19.9 mg, 0.060 mmol, 19.7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.67 (d, J =9.0 Hz, 1H), 7.18 (d, J =2.3 Hz, 1H), 7 .13 (dd, J =8.7, 2.7 Hz, 2H), 3.85 (s, 3H); MS (CIAD ^- ) m/z 328 [MH] ^- .

Example 8 5-[1-Fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 107)

In a 4 ml tube with a septum screw cap, the product of example 1G (0.1 g, 0.215 mmol), sodium tert -butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 µmol) and BrettPhos (3.46 mg, 6.45 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (2 ml) and a solution of methylamine in tetrahydrofuran (0.215 ml, 2 M, 0.430 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at room temperature, and then heated to 100°C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, quenched with 1 M hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-1-fluoro-7- (methylamino)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, a viscous orange oil which was used for the next reaction without purification. MS (CIAD ^- ) m/z 414 [MH] ^- .

To a suspension of the crude intermediate 5-[3-(benzyloxy)-1-fluoro-7-(methylamino)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione in dichloromethane (2 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (1.29 ml, 1 M, 1.29 mmol) along the wall of the flask so that the internal temperature remained below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before re-cooling to -78°C. The reaction was quenched by adding ethyl acetate (1 ml) followed by anhydrous ethanol (0.5 ml). The mixture was warmed to room temperature and then concentrated under reduced pressure. The crude residue was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 µm 100 Å AXIA (30 mm × 75 mm) column with a gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at flow rate 50 ml/minute (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 minutes linear gradient 95-5% A) to give the title compound (0.0136 g, 0.040 mmol, 18.6% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.45 (d, J=8.8 Hz, 1H), 6.93 (dd, J=8.9, 2.3 Hz, 1H), 6.89 (s, 1H), 6.56 (d, J=2.3 Hz, 1H), 5.93-5.80 (m, 1H), 4.07 (s, 2H), 2.76-2.72 (m, 3H); MS (ESI ^- ) m/z 324 [MH] ^- .

Example 9: 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione (Compound 108)

Cesium carbonate (0.243 g, 0.746 mmol) as a solid, and the resulting suspension was heated to 60°C. After 1 hour the reaction mixture was cooled to room temperature, quenched with 2 M hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (3×1 ml). The combined aqueous washings were back-extracted with ethyl acetate (1 mL) and the combined organic layers were washed with 4:1 brine/1M hydrochloric acid, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give t -butyl 4-( 2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)piperidine- 1-carboxylate, dark gel, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 612 [MH] ^- .

To a suspension of the crude intermediate tert -butyl 4-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene -2-yl]oxy}ethyl)piperidine-1-carboxylate in dichloromethane (2 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (2.49 ml, 1 M, 2.49 mmol) so that the internal the temperature remained below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before re-cooling to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (0.5 ml), warmed to room temperature and concentrated under reduced pressure to give a tan solid. The crude solid was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [Phenomenex® Luna® 10 µm C18(2) 250 x 30 mm column, flow rate 100 ml/min, gradient 5-95% acetonitrile in buffer (0.010 M aqueous ammonium acetate)] . The HPLC-purified product was further purified by trituration with 50% v/v. with a mixture of dichloromethane and acetonitrile (3 ml) to give the title compound (0.066 g, 0.155 mmol, 64.9% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.66 (d, J=9.0 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7 .11 (dd, J=9.0, 2.5 Hz, 1H), 7.03 (s, 1H), 4.13 (t, J=6.1 Hz, 2H), 4.09 (s, 2H), 2.89-2.76 (m, 1H), 1.90 (s, 3H), 1.86 (s, 2H), 1.82-1.69 (m, 3H), 1.34 (td, J=12.9, 12.1, 8.7 Hz, 2H); MS (ESI ^- ) m/z 422 [MH] ^- .

Example 10: 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1 λ ^6.2 ,5-thiadiazolidin-1,1,3-trione (Compound 109)

Example 10A: 5-[3-(benzyloxy)-1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}naphthalene-2-yl]-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione

( E )-diazen-1,2-diylbis(piperidin-1-ylmethanone) (219 mg, 0.870 mmol). The reaction was purged with N ₂ at 0° C. for 5 minutes followed by the addition of tri- n -butylphosphine (0.215 mL, 0.870 mmol). The reaction was stirred at 45°C for 14 hours. Volatiles were removed under reduced pressure and the residue was subjected to column chromatography (SiO ₂ , dry load with diatomaceous earth, 10% methanol in dichloromethane) to give the title compound (24 mg, 0.044 mmol, 18% yield) as a beige solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.68 (d, J=9.1 Hz, 1H), 7.25 (d, J=2.6 Hz, 1H), 7 .17 (dd, J=9.0, 2.5 Hz, 1H), 7.04 (s, 1H), 4.30 (wide, 1H), 4.24 (wide, 1H), 4.09 ( s, 2H), 3.06-2.77 (m, 4H), 2.23-1.98 (m, 2H), 1.46-1.37 (broad, 1H), 1.05 (d, J=6.2 Hz, 6H); MS (CIAD-) m/z 454.13 [M-CH ₂ C ₆ H ₅ -H] ^- , 544 [MH] ^- .

Example 10B: 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1 λ ^6.2 ,5-thiadiazolidin-1,1,3-trione

The product from Example 10A (22 mg, 0.040 mmol) and 1,2,3,4,5-pentamethylbenzene (17.93 mg, 0.121 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (5 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.121 ml, 0.121 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at -77°C with dichloromethane:methanol=9:1 (0.5 ml), and then the mixture was slowly warmed to room temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [column Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ (250 mm × 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (7 mg, 0.015 mmol, 38% yield) . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.68 (d, J=9.1 Hz, 1H), 7.25 (d, J=2.6 Hz, 1H), 7 .17 (dd, J=9.0, 2.5 Hz, 1H), 7.04 (s, 1H), 4.30 (wide, 1H), 4.24 (wide, 1H), 4.09 ( s, 2H), 3.06-2.77 (m, 4H), 2.23-1.98 (m, 2H), 1.46-1.37 (broad, 1H), 1.05 (d, J=6.2 Hz, 6H); MS (CIAD-) m/z 454.13 [MH] ^- .

Example 11 5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 110)

Example 11A: tert-butyl 3-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene-2- yl]oxy}methyl)-3-fluoropyrrolidine-1-carboxylate

To a solution of the product of example 1H (100 mg, 0.249 mmol) and tert -butyl 3-fluoro-3-(hydroxymethyl)pyrrolidine-1-carboxylate (163 mg, 0.746 mmol) in tetrahydrofuran (THF) (5 ml) at 0°C ( E )-diazen-1,2-diylbis(piperidin-1-ylmethanone) (219 mg, 0.870 mmol) was added. The reaction was purged with N ₂ at 0° C. for 5 minutes followed by the addition of tri- n -butylphosphine (0.215 mL, 0.870 mmol). The reaction was stirred at 45°C for 14 hours. Volatiles were removed under reduced pressure and the residue was subjected to column chromatography (SiO ₂ , dry load diatomaceous earth, 10% methanol in dichloromethane) to give the title compound (48 mg, 0.080 mmol, 32% yield). MS (CIAD-) m/z 602 [MH] ^- .

Example 11B: 5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trion

The product from Example 11A (45 mg, 0.075 mmol) and 1,2,3,4,5-pentamethylbenzene (33.2 mg, 0.224 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (5 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1M solution of trichloroborane (0.224 ml, 0.224 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at -77°C with dichloromethane:methanol=9:1 (0.5 ml), and then slowly warmed to room temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [column Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ (250 mm × 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (9 mg, 0.022 mmol, 29% yield) . ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.63 (d, J=69.3 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7 .28 (d, J=2.6 Hz, 1H), 7.19 (dd, J=9.0, 2.6 Hz, 1H), 7.06 (s, 1H), 4.57-4, 41 (s, 2H), 4.10 (s, 2H), 3.73-3.48 (m, 4H), 2.43-2.20 (m, 2H); MS (CIAD-) m/z 411.89 [MH] ^- .

Example 12: 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanonitrile ( Connection 111)

Example 12A: 5-{[6-(Benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} pentanonitrile

A mixture of the product of example 1H (100 mg, 0.249 mmol), cesium carbonate (162 mg, 0.497 mmol) in N,N -dimethylformamide (2 ml) was stirred at room temperature for 14 hours. The reaction mixture was filtered and purified by preparative HPLC [Phenomenex® Luna® 10 μm C18 column (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid acid at a flow rate of 50 ml/minute (0-1 min 10% A, 1-20 min linear gradient 10-100%) to give the title compound (80 mg, 0.165 mmol, 67% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.86-7.78 (m, 1H), 7.57-7.48 (m, 2H), 7.42 (s, 1H ), 7.41-7.36 (m, 2H), 7.36-7.31 (m, 1H), 7.31-7.25 (m, 2H), 5.24 (s, 2H), 4.50 (s, 2H), 4.15 (t, J=6.2 Hz, 2H), 2.61 (t, J=7.1 Hz, 2H), 1.87 (m, 2H), 1.82-1.70 (m, 2H); MS (CIAD ^- ) m/z 482 [MH] ⁺ .

Example 12B: 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ 6,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanonitrile

To a mixture of the product of Example 12A (75 mg, 0.155 mmol) and pentamethylbenzene (115 mg, 0.776 mmol) in dichloromethane (2 mL), cooled to -78°C, was added dropwise a solution of boron trichloride (1 M, 0.931 mL, 0.931 mmol ) in dichloromethane for 5 minutes. After 30 minutes the reaction mixture was quenched with 2 N HCl (0.5 ml). The mixture was extracted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC on a Phenomenex® Luna® 10 μm C18 column (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at speed flow 50 ml/minute (0-1 min 10% A, 1-20 min linear gradient 10-100%) to give the title compound (40 mg, 0.102 mmol, 65.6% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.27 (s, 1H), 7.71 (dd, J=9.1, 1.4 Hz, 1H), 7.25- 7.16 (m, 2H), 7.07 (s, 1H), 4.44 (s, 2H), 4.12 (t, J=6.2 Hz, 2H), 2.60 (t, J =7.1 Hz, 2H), 1.87 (dc, J=8.5, 6.4 Hz, 2H), 1.76 (dc, J=9.9, 7.1 Hz, 2H); MS (CIAD ^- ) m/z 392 [MH] ⁺ .

Example 13 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione (Compound 112)

Example 13A: 5-{3-(benzyloxy)-1-fluoro-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trion

A mixture of the product of example 1H (84 mg, 0.2 mmol), 1-(2-chloroethyl)piperidine (94 mg, 0.640 mmol) and cesium carbonate (235 mg, 0.720 mmol) in dimethylformamide (1 ml) was stirred at 75°C within 2 hours. The solution was filtered and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with dichloromethane then dichloromethane/methanol (10:1) to give the title compound (65 mg, 0.127 mmol, 63% yield) as a solid. MS (ESI ⁺ ) m/z 514 [M+H] ⁺ .

Example 13B: 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione

Trichloroborane (1168 μl, 1168 μl, 1.168 mmol, 1.0 M in dichloromethane). The mixture was stirred at -78°C for 40 minutes. At -78°C was added methanol (3 ml). The mixture was stirred for 5 minutes at room temperature, then concentrated under reduced pressure. The solid was washed with heptane (4×5 ml), then dissolved in methanol (0.5 ml) and N,N -dimethylformamide (3 ml). The crude material was purified by preparative HPLC [YMC TriArt™ C18 hybrid 20 µm column, 25 x 150 mm, flow rate 80 ml/min, 5-100% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide )] to give the title compound (30 mg, 0.071 mmol, 61% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.52 (br s, 1H), 7.71 (d, J=8 Hz, 1H), 7.28 (d, J= 2 Hz, 1H), 7.19 (dd, J=8, 2 Hz, 1H), 7.05 (br s, 1H), 4.42 (m, 2H), 4.09 (s, 2H) , 3.46 (m, 4H), 3.00 (m, 2H), 1.72 (m, 4H), 1.47 (m, 2H); MS (ESI ^- ) m/z 422 [MH] ^- .

Example 14: 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 113)

Example 14A: tert-Butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] -2,5-dihydro-1H-pyrrole-1-carboxylate

To the product of example 1G in dioxane (5 ml) was added tert -butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1 H -pyrrole -1-carboxylate (381 mg, 1.290 mmol) and sodium carbonate (1.290 ml, 2.58 mmol). Tetrakis(triphenylphosphine)palladium (0) (99 mg, 0.086 mmol) was added and the reaction mixture was purged with N ₂ for 5 minutes. The mixture was heated at 100° C. overnight. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography (diatomite dry load, 5% CH ₃ OH in CH ₂ Cl ₂ ) to give the title compound (346 mg, 0.625 mmol, 73% yield) as a yellow solid ¹ H (500 MHz, DMSO- d ₆ ) 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 (CIAD-) m/z 551 [MH] ^- .

Example 14B: 5-[3-(Benzyloxy)-7-(2,5-dihydro-1H-pyrrol-3-yl)-1-fluoronaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione

To a solution of the product of example 14A (100 mg, 0.181 mmol) in dichloromethane (2 ml) was added 2,2,2-trifluoroacetic acid (1 ml, 3.61 mmol). The mixture was stirred for 30 minutes at room temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [column Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ (250 mm × 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (60 mg, 0.132 mmol, 73% yield) . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.86 (d, J=3.7 Hz, 2H), 7.60-7.48 (m, 2H), 7.46- 7.27 (m, 5H), 6.60 (t, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.50 (k, J=2.3 Hz, 2H), 4.19 (dt, J=5.0, 2.5 Hz, 2H), 4.10 (s, 2H); MS (CIAD-) m/z 452 [MH] ^- .

Example 14C: 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoronaphthalen-2-yl}-1 λ ⁶ .2 ,5-thiadiazolidin-1,1,3-trione

To a solution of the product of example 14B (88 mg, 0.194 mmol) in dichloromethane (5 ml) was added cyclopropanesulfonyl chloride (0.071 ml, 0.582 mmol) at room temperature, followed by N,N -diisopropyethylamine (0.102 ml, 0.582 mmol). The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure and the residue was subjected to column chromatography (SiO ₂ , dry diatomaceous earth load, 5% CH ₃ OH in CH ₂ Cl ₂ ) to give the title compound (77 mg, 0.138 mmol, 71% yield) as beige solid. MS (CIAD-) m/z 555 [MH] ^- .

Example 14D: 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3 - hydroxynaphthalen-2-yl}-1 λ ^6.2.5 -thiadiazolidin-1,1,3-trione

A solution of the product of example 14C (66 mg, 0.118 mmol) and 1,2,3,4,5-pentamethylbenzene (52.6 mg, 0.355 mmol) in dichloromethane (5 ml) was purged with nitrogen gas for 5 minutes. The solution was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.355 ml, 0.355 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at -77°C with dichloromethane:methanol=2:1 (0.5 ml), and then slowly warmed to room temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [column Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ (250 mm × 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (25 mg, 0.053 mmol, 45% yield) as a beige solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.87 (s, 1H), 7.14 (s, 1H), 7.03-6.99 (m, 2H), 6, 89 (s, 1H), 6.46 (t, J=2.1 Hz, 1H), 4.62-4.55 (m, 2H), 4.29 (dt, J=6.9, 3, 0 Hz, 2H), 4.03 (s, 2H), 2.82-2.71 (m, 1H), 0.97 (dt, J=5.4, 2.8 Hz, 2H), 0, 96-0.86 (m, 2H); MS (CIAD-) m/z 465 [MH] ^- .

Example 15 5-{1-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 114)

Cesium carbonate (0.311 g, 0.954 mmol) as a solid, and the resulting suspension was heated to 60°C. After 3.5 hours the reaction was cooled to room temperature, quenched with 2 M hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (3×1 ml). The combined aqueous washings were back-extracted with ethyl acetate (1 mL) and the combined organic layers were washed with 4:1 brine/1M hydrochloric acid, then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give t -butyl 4-({ [6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)piperidine-1-carboxylate , which was used for the next reaction without purification. MS (CIAD ^- ) m/z 598 [MH] ^- .

Into a suspension of tert -butyl 4-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] hydroxy}methyl)piperidine-1-carboxylate in dichloromethane (2 ml) at -78°C was added slowly a solution of boron trichloride in dichloromethane (2.38 ml, 1 M, 2.38 mmol) along the wall of the flask so that the internal temperature remained below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (0.5 ml), warmed to room temperature and concentrated under reduced pressure to give a tan solid. The crude solid was suspended in ethyl acetate (5 ml) and sonicated for 30 seconds to obtain a suspension. The solid was collected by filtration and washed with ethyl acetate (2 ml). The solid was dissolved in dimethyl sulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [Waters XBridge™ C18 5 µm OBD column, 30 x 100 mm, flow rate 40 ml/min, gradient 3-30% methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 ammonium hydroxide)] to give the title compound (0.066 g, 0.155 mmol, 65% yield), ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.65 (dd, J=9, 1, 1.5 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7.13 (dd, J=9.0, 2.5 Hz, 1H), 7.02 ( s, 1H), 4.11 (s, 2H), 3.96 (s, 2H), 3.27 (s, 2H), 2.90 (td, J=12.8, 3.0 Hz, 2H ), 2.08 (d, J=11.0 Hz, 1H), 1.95 (dd, J=14.6, 3.5 Hz, 2H), 1.58-1.37 (m, 2H) ; MS (ESI ^- ) m/z 408 [MH] ^- .

Example 16 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanonitrile (Compound 115)

Example 16A: 5-bromo-3,3-dimethylpentanonitrile

To a solution of 5-bromo-3,3-dimethylpentanoic acid (0.5 g, 2.391 mmol) in dichloromethane (10 ml) was added chlorosulfonyl isocyanate (0.208 ml, 2.391 mmol) dropwise. The resulting solution was stirred for 15 minutes at room temperature and then heated to an internal temperature of 40°C. After 2 hours, gas evolution ceased and the reaction mixture was cooled to 0°C. N,N -diisopropylethylamine was slowly added via syringe so that the internal temperature remained below 7°C. The resulting solution was then warmed to room temperature and stirred for 1 hour. The reaction was quenched with 1 M sodium bisulfate (5 ml) and the layers were separated. The aqueous layer was extracted with dichloromethane (DCM) (2×5 ml) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude oil was dissolved in 50% v/v. a mixture of heptanes and ethyl acetate (5 ml), and the resulting solution was washed with 1 M sodium carbonate (2 x 5 ml), then with brine (2 ml), then dried over sodium sulfate and filtered through silica (2 g). The solid was washed with heptanes (5 mL) and the filtrate was concentrated under reduced pressure to give the title compound (0.33 g, 1.73 mmol, 72.5% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.43-3.29 (m, 2H), 2.28 (s, 2H), 2.08-1.96 (m, 2H), 1.10 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ ppm 117.72, 44.58, 34.22, 30.67, 26.39.

Example 16B: 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3 ,3-dimethylpentanonitrile

Cesium carbonate (0.243 g, 0.746 mmol) was added as a solid and the resulting suspension was heated to 60°C. After 3 hours the reaction was cooled to room temperature, quenched with 2 N hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (3×1 ml). The combined aqueous washing material was back extracted with ethyl acetate (1 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-{[6-(benzyloxy)-8-fluoro-7-(1, 1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanonitrile, which was used in the next step without purification. MS (CIAD ^- ) m/z 510 [MH] ^- .

In suspension 5-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3 ,3-dimethylpentanonitrile in dichloromethane (2 ml) at -78°C, a solution of boron trichloride in dichloromethane (0.75 ml, 1 M, 0.75 mmol) was slowly added along the wall of the flask so that the internal temperature remained below -70°C . The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (0.5 ml), warmed to room temperature and concentrated under reduced pressure to give a tan solid. The residue was taken up in dimethyl sulfoxide/methanol and filtered through a glass microfiber filter separator. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 µm 100 Å AXIA™ (30 mm × 75 mm) column with a gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at speed flow 50 ml/minute (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 (0.0100 g, 0.023 mmol, 18.2% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.66 (dd, J=9.1, 1.5 Hz, 1H), 7.23 (d, J=2.6 Hz, 1H), 7.12 (dd, J=9.0, 2.5 Hz, 1H), 7.02 (s, 1H), 4.15 (t, J=6.9 Hz, 2H), 4, 09 (s, 2H), 2.59 (s, 2H), 1.84 (t, J=6.9 Hz, 2H), 1.10 (s, 6H); MS (ESI ^- ) m/z 420 [MH] ^- .

Example 17 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 116)

In a 4 ml tube with a septum screw cap, the product of example 1G (0.1 g, 0.215 mmol), sodium tert -butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 µmol) and BrettPhos (3.46 mg, 6.45 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (2 ml) and 3,3-dimethylbutan-1-amine (0.044 g, 0.430 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at room temperature, and then heated to 100°C. After 30 minutes at 100°C the reaction mixture was cooled to room temperature, then extinguished with 1 M hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-7-[(3, 3-dimethylbutyl)amino]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 484 [MH] ^- .

To a suspension of crude 5-{3-(benzyloxy)-7-[(3,3-dimethylbutyl)amino]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione in dichloromethane (2 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (1.29 ml, 1 M, 1.29 mmol) along the wall of the flask so that the internal temperature remained below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (0.5 ml), warmed to room temperature and concentrated under reduced pressure to give a brown solid. The crude product was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 µm 100 Å AXIA™ (30 mm × 75 mm) column with a gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at speed flow 50 ml/minute (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 (0.0165 g, 0.040 mmol, 18.6% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.44 (dd, J=9.1, 1.7 Hz, 1H), 6.94 (dd, J=9.0, 2 .3 Hz, 1H), 6.87 (s, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.74 (t, J=5.4 Hz, 1H), 4, 07 (s, 2H), 3.07 (dt, J=10.4, 5.2 Hz, 2H), 1.57-1.49 (m, 2H), 0.97 (s, 9H); MS (ESI ^- ) m/z 394 [MH] ^- .

Example 18 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 117)

Example 18A: 5-[3-(Benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a mixture of the product of Example 1F (300 mg, 0.603 mmol) in dimethylformamide (6.73 ml) was added Selectfluor® (256 mg, 0.724 mmol) and the homogeneous light yellow solution was heated to 65°C. After 90 minutes the mixture was cooled to room temperature and the excess oxidant was quenched with a solution of sodium thiosulfate pentahydrate (404 mg, 1.63 mmol) in water (3.3 ml). After stirring for 15 minutes, water (10 ml) was added and the mixture was extracted with ethyl acetate (3×10 ml). The combined organic fractions were washed with saturated aqueous ammonium chloride (2 x 10 ml) and brine (1 x 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] ⁺ .

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, sodium methoxide solution was added with a syringe (207 μl, 0.905 mmol) (25 wt.% in methanol), and the resulting solution was stirred at room temperature. After 5 minutes 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 (3×1 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 SiO ₂ , CH ₂ Cl ₂ to 10% methanol/CH ₂ Cl ₂ ) to give the title compound along with minor inseparable impurities. The product was carried to the next step without further purification. MS (APCI ⁺ ) m/z 484 [M+H] ⁺ .

Example 18B: 5-[3-(benzyloxy)-1,4-difluoro-7-methoxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A mixture of the product of Example 18A (301 mg, 0.623 mmol), RockPhos Pd G3 (16.1 mg, 0.019 mmol) and cesium carbonate (609 mg, 1.87 mmol) was placed under vacuum and stirred for 5 minutes, then the flask was filled with nitrogen and the prepared mixture of N,N -dimethylformamide (3.11 ml) and anhydrous methanol (126 μl, 3.11 mmol) was added. The resulting slurry was degassed with five vacuum/nitrogen backfill cycles and then heated to an internal temperature of 80°C. After 15 minutes 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 (2×5 ml). The combined organics were washed with saturated aqueous ammonium chloride (4×5 ml), then dried over sodium sulfate, filtered and concentrated to give a viscous dark oil. The residue was purified by flash column chromatography (12 g SiO ₂ , CH ₂ Cl ₂ to 10% methanol/CH ₂ Cl ₂ ) to give the title compound along with minor inseparable impurities. The product was carried to the next step without further purification. MS (CIAD ⁺ ) m/z 435 [M+H] ⁺ .

Example 18C: 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A mixture of the product of Example 18B (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 dry nitrogen. Thereafter, a 1 M solution of boron trichloride (178 μl, 0.178 mmol) in CH ₂ Cl ₂ was added dropwise over 15 minutes so that the internal temperature did not rise above -72°C. After 15 minutes, the reaction was quenched at -75°C CH ₂ Cl ₂ /methanol (10:1, 230 μl) with transfer through a cannula under nitrogen atmosphere. Thereafter, the mixture was slowly warmed to room temperature under a nitrogen atmosphere. Volatiles were removed in vacuo to give a brown solid which was purified by HPLC (Phenomenex® Luna® 10 μM C18(2) 100 Å column, AXIA™ (00G-4253-U0-AX), 250 x 300 mm, flow rate 50 ml/minute, 5-95% gradient of acetonitrile in buffer (0.025 M aqueous ammonium acetate) to give the title compound (10.3 mg, 0.030 mmol, 34% yield) as a white solid.1 ^H NMR (CD ₃ OD) 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 (ESI ^- ) m/z 343 [MH] ^- .

Example 19 5-{1-fluoro-3-hydroxy-7-[( ² H ₃ )methyloxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 118)

Example 19A: 5-{3-(benzyloxy)-1-fluoro-7-[( ² H ₃ )methyloxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A mixture of the product of Example 1H (200 mg, 0.497 mmol), iodomethane- d ₃ (68.4 mg, 0.472 mmol) and cesium carbonate (324 mg, 0.994 mmol) in N,N -dimethylformamide (2 mL) was stirred at ambient temperature within 2 hours. The reaction mixture was purified by preparative HPLC on a Phenomenex® Luna® 10 μm C18 column (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) with 0.1% trifluoroacetic acid at flow rate of 50 ml/minute (0-1 min 10% A, 1-20 min linear gradient 10-75%) to give the title compound (60 mg, 0.143 mmol, 28.8% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.81 (dt, J=8.2, 1.4 Hz, 1H), 7.54-7.49 (m, 2H), 7.42 (s, 1H), 7.41-7.36 (m, 2H), 7.37-7.31 (m, 1H), 7.27 (d, J=8.3 Hz, 2H) , 5.24 (s, 2H), 4.48 (s, 2H); MS (CIAD-) m/z 418 [MH] ^- .

Example 19B: 5-{1-fluoro-3-hydroxy-7-[( ² H ₃ )methyloxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a mixture of the product of Example 19A (56 mg, 0.134 mmol) and pentamethylbenzene (99 mg, 0.668 mmol) in dichloromethane (2 mL) cooled to -78°C was added dropwise a solution of boron trichloride (0.801 mL, 0.801 mmol) in dichloromethane within 5 minutes. After 30 minutes the reaction was quenched with 2 N HCl (0.5 ml). The reaction mixture was extracted with ethyl acetate. The organic fractions were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC on a Phenomenex® Luna® 10 μm C18 column (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) with 0.1% trifluoroacetic acid at speed flow 50 ml/minute (0-1 min 10% A, 1-20 min linear gradient 10-100%) to give the title compound (30 mg, 0.091 mmol, 68.2% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.81 (dt, J=8.2, 1.4 Hz, 1H), 7.54-7.49 (m, 2H), 7.42 (s, 1H), 7.41-7.36 (m, 2H), 7.37-7.31 (m, 1H), 7.27 (d, J=8.3 Hz, 2H) , 5.24 (s, 2H), 4.48 (s, 2H); MS (CIAD-) m/z 328 [MH] ^- _.

Example 20 5-[1-Fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 119)

Example 20A: 5-[3-(Benzyloxy)-1-fluoro-7-(2-methoxyethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

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 minutes. The solution was filtered and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with dichloromethane followed by dichloromethane:methanol (10:1) to give the title compound (100 mg, 0.217 mmol, 90% yield) as a solid. 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 (br 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 (ESI ^- ) m/z 459 [MH] ^- .

Example 20B: 5-[1-Fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Trichloroborane (869 μl, 0.869 mmol, 1.0 M in dichloromethane). The mixture was stirred at -78°C for 40 minutes. At -78°C was added methanol (5 ml). The mixture was stirred for 5 minutes at room temperature and then concentrated under reduced pressure. The resulting solid was washed with heptane (5 ml x 4), then dissolved in methanol (0.5 ml) and N,N -dimethylformamide (3 ml). The mixture was purified by preparative HPLC [YMC TriArt™ C18 hybrid 20 µm column, 25 x 150 mm, flow rate 80 ml/min, 5-100% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide) ] to give the title compound (35 mg, 0.095 mmol, 44% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.27 (br s, 1H), 7.67 (d, J=8 Hz, 1H), 7.18 (d, J= 2 Hz, 1H), 7.14 (dd, J=8, 2 Hz, 1H), 7.03 (br s, 1H), 4.19 (m, 2H), 4.09 (s, 2H) , 3.71 (m, 2H), 3.33 (s, 3H); MS (ESI ^- ) m/z 369 [MH] ^- _.

Example 21 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2 ,2-dimethylbutanonitrile (Compound 120)

Example 21A: 4-{[6-(Benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} -2,2-dimethylbutanonitrile

To a solution of the product of example 1H (100 mg, 0.249 mmol) in dimethylformamide (3 ml) was added sodium hydride (21.87 mg, 0.547 mmol) in three parts at room temperature. The mixture was stirred for 30 minutes until the end of gas evolution. A solution of 4-bromo-2,2-dimethylbutanonitrile (96 mg, 0.547 mmol) in N,N -dimethylformamide (2 ml) was slowly added to the reaction mixture. The mixture was stirred overnight at room temperature. Methanol (2 ml) was added, the volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , 10% CH ₃ OH in CH ₂ Cl ₂ ) to give the title compound (65 mg, 0.131 mmol, 53% yield ). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.77 (dd, J=9.1, 1.4 Hz, 1H), 7.59-7.50 (m, 2H), 7.44-7.26 (m, 5H), 7.20 (dd, J=9.0, 2.5 Hz, 1H), 5.22 (s, 2H), 4.28 (t, J= 6.5 Hz, 2H), 4.09 (s, 2H), 3.17 (d, J=5.2 Hz, 1H), 2.12-2.05 (m, 2H), 1.41 ( s, 6H); MS (CIAD-) m/z 496 [MH] ^- .

Example 21B: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2 ,2-dimethylbutanonitrile

The product from Example 21A (56 mg, 0.113 mmol) and 1,2,3,4,5-pentamethylbenzene (50.1 mg, 0.338 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (5 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.338 ml, 0.338 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at -77°C with dichloromethane:methanol=2:1 (1 ml), and then the mixture was slowly warmed to room temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (28 mg, 0.069 mmol, 61% yield) as a white solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.68 (dd, J=9.1, 1.4 Hz, 1H), 7.25 (d, J=2.6 Hz, 1H), 7.13 (dd, J=9.0, 2.5 Hz, 1H), 7.04 (d, J=1.3 Hz, 1H), 4.29-4.18 (m, 2H ), 4.10 (s, 2H), 2.11-2.05 (m, 2H), 1.41 (s, 6H); MS (CIAD-) m/z 405 [MH] ^- .

Example 22 5-{7-[2-(3-aminobicyclo[1,1,1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 121)

Example 22A: 2-{3-[(tert-butoxycarbonyl)amino]bicyclo[1,1,1]pentan-1-yl}ethyl methanesulfonate

To a mixture of tert -butyl (3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (0.341 g, 1.5 mmol) and triethylamine (0.304 g, 3.00 mmol) in dichloromethane (4 ml) at 0°C was added methanesulfonyl chloride (0.180 g, 1.575 mmol) in dichloromethane (1 ml). The mixture was stirred for 40 minutes at room temperature. The mixture was diluted with dichloromethane (60 ml) and washed with water (20 ml × 2). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (460 mg, 1.50 mmol, 100% yield) as a solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.39 (br s, 1H), 4.16 (t, J=8 Hz, 2H), 3.15 (s, 3H) , 1.89 (t, J=8 Hz, 2H), 1.81 (s, 6H), 1.37 (s, 9H); MS (ESI ⁺ ) m/z 250 [M- tert- Bu+H] ⁺ .

Example 22B: tert-butyl [3-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene -2-yl]oxy}ethyl)bicyclo[1,1,1]pentan-1-yl]carbamate

A mixture of the product of example 1H (62.8 mg, 0.15 mmol), the product of example 22A (110 mg, 0.360 mmol) and cesium carbonate (161 mg, 0.495 mmol) in dimethylformamide (1 ml) was stirred at 75°C for 1 .5 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with dichloromethane followed by dichloromethane:methanol (20:1) to give the title compound (70 mg, 0.11 mmol, 74% yield) as a solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.78 (d, J=8 Hz, 1H), 7.57 (d, J=8 Hz, 2H), 7.49 (s , 1H), 7.42 (d, J=2 Hz, 1H), 7.28-7.38 (m, 4H), 7.21 (dd, J=8, 2 Hz, 1H), 5.21 (br s, 2H), 4.10 (t, J=8 Hz, 2H), 3.93 (br s, 2H), 2.00 (t, J=8 Hz, 2H), 1.84 (s, 6H), 1.37 (s, 9H); MS (ESI ^- ) m/z 626 [MH] ^- .

Example 22C: 5-{7-[2-(3-aminobicyclo[1,1,1]pentan-1-yl)ethoxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1 λ ⁶ , 2,5-thiadiazolidin-1,1,3-trione

A mixture of the compound from Example 22B (88 mg, 0.144 mmol) and trifluoroacetic acid (1148 mg, 10.07 mmol) in dichloromethane (1.5 ml) was stirred at room temperature for 20 minutes. The mixture was concentrated. The residue was purified by silica gel flash column chromatography, eluting with dichloromethane, then dichloromethane/methanol (7:1) to give the title compound (90 mg, 0.144 mmol, 100 yield) as the trifluoroacetate salt. MS (ESI ⁺ ) m/z 512 [M+H] ⁺ .

Example 22D: 5-{7-[2-(3-aminobicyclo[1,1,1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ^.2 , 5-thiadiazolidin-1,1,3-trione

Trichloroborane (1535 µl, 1.535 mmol, 1.0 M in dichloromethane). The mixture was stirred at -78°C for 10 minutes, then at 0°C for 20 minutes. At 0° C., methanol (6 ml) was added. The ice bath was removed, the mixture was stirred for 5 minutes at room temperature and then concentrated under reduced pressure. The resulting solid was washed with heptane (5 ml x 4) and dichloromethane (2 ml x 4), purified by silica gel flash column chromatography, eluted with dichloromethane followed by dichloromethane:methanol (5:1) to give the indicated in title compound (32 mg, 0.076 mmol, 59% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.77 9br s, 2H), 7.67 (d, J=8 Hz, 1H), 7.19 (d, J=2 Hz , 1H), 7.12 (dd, J=8, 2 Hz, 1H), 7.16 (s, 1H), 4.14 (br s, 2H), 4.09 (t, J=8 Hz , 2H), 2.04 (t, J=8 Hz, 2H), 1.94 (s, 6H); MS (ESI ^- ) m/z 420 [MH] ^- .

Example 23: 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 122)

In a 4 ml tube with a septum screw cap, the product of example 1G (0.1 g, 0.215 mmol), sodium tert -butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 µmol) and BrettPhos (3.46 mg, 6.45 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (2 ml) and N,N -dimethylethylenediamine (0.047 ml, 0.430 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at room temperature, and then heated to 100°C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, quenched with 1 M hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-7-{[2- (dimethylamino)ethyl]amino}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 471 [MH] ^- .

Into a suspension of 5-[3-(benzyloxy)-7-{[2-(dimethylamino)ethyl]amino}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione in dichloromethane (2 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (2.15 ml, 1 M, 2.15 mmol) along the wall of the flask so that the internal temperature remained below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (0.5 ml) and warmed to room temperature to obtain a suspension. The resulting solid was collected by filtration, then washed with ethyl acetate (2×1 ml) and 50% v/v. with a mixture of acetonitrile and ethyl acetate (1 ml) and dried in vacuo (15 mbar) at 50° C. to constant weight to give the title compound (0.0524 g, 0.125 mmol, 58.7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.53 (d, J=8.8 Hz, 1H), 7.02 (dd, J=9.0, 2.2 Hz, 1H), 6.96 (s, 1H), 6.80 (s, 1H), 4.25 (br s, 2H), 3.49 (t, J=6.2 Hz, 2H), 3, 31 (t, J=5.9 Hz, 2H), 2.83 (s, 6H); MS (ESI ^- ) m/z 381 [MH] ^- .

Example 24: 5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)(4,4- ² H ₂ )-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 123)

Example 24A: methyl {[3-(benzyloxy)-7-methoxynaphthalen-2-yl]amino}( ² H ₂ )acetate

Methyl bromoacetate-2,2- d ₂ ( 0.452 ml, 4.77 mmol) with 0.5 eq. D ₂ O (0.032 ml, 1.592 mmol). The mixture was stirred at 60°C for 2 hours, after which it was left to cool to ambient temperature. The reaction was quenched with 10% acetic acid- d ₄ in D ₂ O (3 ml) and then diluted and extracted with ethyl acetate (50 ml). The organic layer was washed with saturated aqueous NH ₄ Cl (3×50 ml) and brine (1×50 ml) and dried over Na ₂ CO ₃ . The mixture was filtered and concentrated under reduced pressure to give the title compound, which was used directly in the next step. MS (APCI ⁺ ) m/z 354 [M+H] ⁺ .

Example 24B: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]amino}( ² H ₂ )acetate

To a stirred solution of the product of Example 24A (0.180 g, 0.509 mmol) in tetrahydrofuran (5.1 mL) was added N -fluoro- N- (phenylsulfonyl)benzenesulfonamide (0.169 g, 0.535 mmol). After 2 hours, Na ₂ SO ₃ (200 mg) was added and the suspension was stirred for 30 minutes. The tetrahydrofuran was removed under a stream of N ₂ and the residue was purified by column chromatography (SiO ₂ , 0-50% ethyl acetate in heptanes) to give the title compound (0.160 g, 0.431 mmol, 85%). MS (CIAD ⁺ ) m/z 372 [M+H] ⁺ .

Example 24C: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl][(t-butoxycarbonyl)sulfamoyl]amino}( ² H ₂ )acetate

A thermally dried 20 ml stirred scintillation vial was filled with CH ₂ Cl ₂ (5 ml) followed by chlorosulfonyl isocyanate (0.075 ml, 0.859 mmol)) under nitrogen. Thereafter, 2-methylpropan-2-( ^2H )ol (0.083 ml, 0.859 mmol) was added dropwise over 10 minutes, after which the reaction was stirred at ambient temperature for 30 minutes. A freshly prepared solution of the product of example 24B (160 mg, 0.430 mmol) and triethylamine (0.180 ml, 1.289 mmol) in dichloromethane (3 ml) was then added dropwise over 2 minutes. The reaction was stirred at room temperature. Then most of the solvent was removed under N ₂ flow and 2 ml of toluene was added. The residue was purified by column chromatography (SiO ₂ , 0-50% ethyl acetate in heptanes) to give the title compound (0.180 g, 0.327 mmol, 76%). MS (CIAD ⁺ ) m/z 451 [M-CO ₂ C(CH ₃ ) ₃ +H] ⁺ , 495 [MC(CH ₃ ) ₃ +H] ⁺ , 569 [M+H ₂ O+H] ⁺ .

Example 24D: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl](sulfamoyl)amino}( ² H ₂ )acetate

Trifluoroacetic acid- d (0.381 ml, 4.90 mmol) was added dropwise to a stirred solution of the product of Example 24C (0.18 g, 0.327 mmol) in CH ₂ Cl ₂ (3 ml). The solution was stirred at ambient temperature. After 1 hour, all volatiles were removed and the residue was purified by column chromatography (SiO ₂ , 0-100% ethyl acetate in heptanes) to give the title compound (0.132 g, 0.293 mmol, 90%). MS (CIAD ⁺ ) m/z 451 [M+H] ⁺ .

Example 24E: 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl](4,4- ² H ₂ )-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3- trion

Before the reaction, a freshly prepared ~1 N DCl solution was prepared by dissolving 265 μl of a 35% (wt in D ₂ O) solution of DCl in D ₂ O to 3 ml. The product of example 24D (0.02 g, 0.044 mmol) was dissolved in deuterated methanol (1 ml) to obtain a suspension. Sodium hydride (8.79 mg, 0.220 mmol) was added slowly at room temperature; the solution became homogeneous with a slightly yellow color. The solution was heated to 60°C and left to mix for 30 minutes. The mixture was carefully quenched with 1 ml DCl in D ₂ O (~1 M) and ethyl acetate (1 ml) was added. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (0.013 g, 0.031 mmol, 70.7%). MS (CIAD ⁺ ) m/z 419 [M+H] ⁺ .

Example 24F: 5-(1-Fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)(4,4-2 ^H 2 ₎ -1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

The product from example 24E (0.121 g, 0.289 mmol) was dissolved in dichloromethane (5 ml) and 1,2,3,4,5-pentamethylbenzene (0.129 g, 0.868 mmol) was added. The mixture was cooled to -78°C and stirred for 5 minutes before adding dropwise boron trichloride (0.636 ml, 0.636 mmol). The mixture was stirred for 30 minutes and methanol- d ₄ (0.125 g, 3.47 mmol) in dichloromethane (0.75 ml) was slowly added along the tube wall. The mixture was stirred for 10 minutes and the ice bath was removed. The mixture was allowed to warm to ambient temperature (a white solid precipitated out of solution) and stirred for 30 minutes. The solvent was removed under N ₂ flow and the residue was purified by reverse phase HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (150 mm × 30 mm); 3-100% gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) over 17 minutes at a flow rate of 50 ml/minute] to give a product which was dissolved in CH ₃ CN:D ₂ O (1:1, 4 ml) and lyophilized to give the title compound as a white powder (44.7 mg, 0.136 mmol, 47%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.67 (d, J =9.3 Hz, 1H), 7.17 (d, J =2.5 Hz, 1H), 7 .13 (dd, J =9.0, 2.4 Hz, 1H), 7.03 (d, J =1.3 Hz, 1H), 3.85 (s, 3H); MS (CIAD ^- ) m/z 327 [MH] ^- .

Example 25: 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 124)

Example 25A: Benzyl 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylate

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 minutes at 23°C . After that, benzyl bromide (84 ml, 705 mmol) was added. After 90 minutes the mixture was poured into H ₂ O (1 L) and extracted with ethyl acetate (4×300 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (3×100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give a brown solid. The crude solid was collected by filtration, suspended with tert -butyl methyl ether/heptanes (1:2, 3×100 ml), then dried in vacuo (12 mbar) at 40°C to give the title compound (122.5 g , 307 mmol, 89% yield as a beige solid. MS (CIAD ⁺ ) m/z 399 [M+H] ⁺ .

Example 25B: 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylic acid

To a suspension of the product of example 25A (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 agitated by mechanical agitation from above and heated to an internal temperature of 68°C. After 15 minutes, the mixture was cooled to room temperature in an ice bath and 6 M HCl (250 ml) was added over 5 minutes. The dirty protein 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) in form of a white solid. MS (APCI ⁺ ) m/z 309 [M+H] ⁺ .

Example 25C: 3-(benzyloxy)-7-methoxynaphthalene-2-amine

To a suspension of the product of example 25B (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 a nitrogen atmosphere, and diphenyl phosphorazidate (62.2 ml, 289 mmol) was added dropwise over 90 minutes with the whole reaction behind a baffle screen. After 5 hours the reaction was cooled to room temperature, diluted with H ₂ O (1.5 L) and extracted with ethyl acetate (3×150 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 was taken to the hydrolysis step without further purification.

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 a nitrogen atmosphere, during which time a homogeneous dark orange solution was formed. After 16 hours, the mixture was cooled to room temperature in an ice bath and H ₂ O (1.5 L) was added slowly over 3 minutes, which resulted in the precipitation of a yellow solid and a simultaneous exothermic transition 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 back-extracted with CH ₂ Cl ₂ (3 x 150 ml) and the combined organic layers were washed with brine (3 x 100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 78.8 g of an orange solid. The solid was suspended in isopropanol (50 ml), collected by filtration, resuspended in isopropanol (1 x 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 25D: methyl {[3-(benzyloxy)-7-methoxynaphthalen-2-yl]amino}acetate

To a mixture of the product of Example 25C (59.2 g, 212 mmol) and potassium carbonate (58.6 g, 424 mmol) in 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 vigorously stirred at room temperature for 5 minutes and then heated to an internal temperature of 60°C. After 70 minutes 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 beige solid. The solid was triturated with heptanes (200 ml). The resulting beige solid was collected by filtration, washed with additional heptanes (2×30 mL) and dried in vacuo (15 mbar) at 35° C. to give the title compound (72.27 g, 206 mmol, 97% yield) as an off-white solid. MS (CIAD+) m/z 352 [M+H] ⁺

Example 25E: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]amino}acetate

To a mixture of the product of Example 25D (30.0 g, 85 mmol) and N -fluorobenzenesulfonimide (26.9 g, 85 mmol) was added tetrahydrofuran (THF) (854 ml) and the resulting homogeneous yellow solution was stirred at room temperature. After 90 minutes, the oxidant residue 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 minutes. After that, ethyl acetate (600 ml) was 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 layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a bright yellow/orange solid. The solids were triturated with t -butyl methyl ether (300 mL), collected by filtration, and the filter cake ( N- (phenylsulfonyl)benzenesulfonamide) was washed with t -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 25F: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl](sulfamoyl)amino}acetate

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) so that the internal temperature remained below 10°C . After stirring for 30 minutes at 0°C, a prepared solution of the product of example 25E (14.55 g, 39.4 mmol) and triethylamine (10.98 ml, 79 mmol) in dichloromethane (68.9 ml) was slowly added via a funnel to adding so that the internal temperature remains below 10°C. After the addition was completed, the addition funnel was washed with dichloromethane (23 ml). The resulting solution was stirred for 30 minutes at 0°C, after which the reaction mixture was quenched with H ₂ O (20 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2×30 ml). The combined organic layers were washed with brine (1×30 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, 2×50 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 cleaning.

Trifluoroacetic acid ( 45.5 ml, 591 mmol), and the resulting dark solution was stirred at room temperature. After 20 minutes, the reaction was quenched by 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; after 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 in vacuo (15 mbar) at 35°C to give the indicated in 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 25G: 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the product of Example 25F (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 stirred the resulting solution at room temperature. After 10 minutes 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 (2×120 ml). The combined organic layers were washed with brine (3×50 ml), then dried over sodium sulfate, filtered and concentrated. The crude 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione was used in the next reaction without further purification.

A mixture of crude intermediate 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (12.28 g, 29. 5 mmol) and pentamethylbenzene (13.11 g, 88 mmol) in dichloromethane (147 ml) were cooled to an internal temperature of -76° C. under dry nitrogen. Thereafter, a 1 M solution of boron trichloride (59.0 ml, 59.0 mmol) in CH ₂ Cl ₂ was added dropwise over 15 minutes so as not to raise the internal temperature more than -72°C. During the addition, the reaction turned dark brown and became homogeneous. An 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 CH ₂ Cl ₂ /methanol (10:1, 140 ml) with transfer through a cannula under nitrogen atmosphere for 15 minutes, then slowly warmed to room temperature over 20 minutes under nitrogen atmosphere. Volatiles were removed in vacuo to give a brown/red solid, which was collected by filtration and suspended with heptanes (5×40 ml) and CH ₂ Cl ₂ (3×40 ml). The crude solid material was suspended in isopropanol (75 ml), heated to dissolve the material, and allowed to cool slowly to room temperature over 1 hour. The solid was collected by filtration, washed with heptanes (2 x 30 ml) and dried in vacuo (15 mbar) at 60° C. to give 5.11 g of a white solid. The mother liquor was concentrated and the process 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 (CD ₃ OD) 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, 1H), 4.56 (s, 2H), 3.89 (s, 3H); MS (ESI ^- ) m/z 325 [MH] ^- .

Example 26: N -(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide (Compound 125)

In a 4 ml tube with a septum screw cap, the product of example 1G (0.15 g, 0.322 mmol), sodium tert -butoxide (0.0.093 g, 0.967 mmol), BrettPhos Pd G3 precatalyst (8.77 mg, 9.67 mmol ) and BrettPhos (5.19 mg, 9.67 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (3 ml) and tert -butyl (2-aminoethyl)carbamate (0.102 ml, 0.645 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at room temperature, and then heated to 100°C. After 30 minutes at 100°C the reaction mixture was cooled to room temperature, then extinguished with 1 M hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give t -butyl (2-{[6-(benzyloxy)-8 -fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)carbamate, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 543 [MH] ^- .

To a solution of crude tert -butyl (2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl ]amino}ethyl)carbamate in dioxane (0.875 ml) was added a solution of HCl in dioxane (0.35 ml, 1.4 mmol, 4 M) and the resulting solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with tert -butyl methyl ether (1.75 ml) to give a suspension. The resulting solid was collected by filtration of methyl tert -butyl methyl ether (2 x 0.875 ml) and dried to give a hygroscopic white solid which rapidly turned to a brown gum upon standing in air. Hydrochloric acid salt of 5-{7-[(2-aminoethyl)amino]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione was used without additional purification for the next reaction. MS (APCI ⁺ ) m/z 445 [M+H] ⁺ .

Into a suspension of crude hydrochloric acid salt 5-{7-[(2-aminoethyl)amino]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione in dichloromethane (1.6 ml) was added 1,2,2,6,6-pentamethylpiperidine (0.235 ml, 1.288 mol). The resulting solution was stirred for 5 minutes at room temperature and then cooled to 0°C. Cyclopropanesulfonyl chloride (0.059 mL, 0.644 mmol) was added dropwise to the cooled solution via syringe. The resulting solution was stirred for 30 minutes and then quenched with water (2 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (3×1 ml). The combined organic layers were washed with 1 M sodium bisulfate (1 ml) and the second aqueous layer was back-extracted with dichloromethane (2 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- (2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ .2, 5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 547 [MH] ^- .

To a suspension of crude N- (2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] amino}ethyl)cyclopropanesulfonamide in dichloromethane (3.5 ml) at -78°C, a solution of boron trichloride in dichloromethane (3.22 ml, 1 M, 3.22 mmol) was slowly added along the wall of the flask so that the internal temperature remained below - 70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml) followed by anhydrous ethanol (0.5 ml) and then warmed to room temperature and concentrated under reduced pressure to give a tan solid. The crude solid was suspended in heptanes (5 ml) and sonicated for 30 seconds to obtain a suspension. The solid was collected by filtration and washed with heptanes (2 ml). The solid was then dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber filter separator. The resulting solution was directly purified by preparative HPLC [Phenomenex® Luna® 10 µm C18(2) 250 x 30 mm column, flow rate 100 ml/min, gradient 5-60% methanol in buffer (0.010 M aqueous ammonium acetate)] to give the title compound (0.0475 g, 0.100 mmol, 47% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.46 (dd, J=9.0, 1.6 Hz, 1H), 6.95 (dd, J=9.0, 2 .4 Hz, 1H), 6.88 (d, J=10.3 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 4.10 (s, 2H), 3, 27-3.21 (m, 2H), 3.21-3.15 (m, 2H), 2.58-2.49 (m, 1H), 0.97-0.85 (m, 4H); MS (ESI ^- ) m/z 457 [MH] ^- .

Example 27: 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione (Compound 126)

In a 4 ml tube with a septum screw cap were combined 3-amino-1-methanesulfonylpyrrolidine (0.71 g, 0.430 mmol), the product of Example 1G (0.1 g, 0.215 mmol), sodium tert -butoxide (0.062 g, 0.645 mmol) , BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 µmol) and BrettPhos (3.46 mg, 6.45 µmol). The solids were placed under vacuum for 5 minutes with stirring and then the tube was filled with nitrogen followed by 1,4-dioxane (2 ml). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at room temperature, and then heated to 100°C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, then quenched with 1 M hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-1-fluoro-7- {[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ⁺ ) m/z 549 [M+H] ⁺ .

To a suspension of crude 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione in dichloromethane (2.3 mL) at -78°C, a solution of boron trichloride in dichloromethane (2.15 mL, 1 M, 2.15 mmol) was slowly added along the wall of the flask so that the internal temperature remained below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml) followed by anhydrous ethanol (0.5 ml) and then warmed to room temperature and concentrated under reduced pressure to give a tan solid. The crude solid was suspended in heptanes (5 ml) and then sonicated for 30 seconds to obtain a suspension. The solid was collected by filtration and washed with heptanes (2 ml). The solid was then dissolved in dimethyl sulfoxide/methanol and filtered through a glass microfiber filter separator. The resulting solution was directly purified by preparative HPLC [Phenomenex® Luna® 10 µm C18(2) 250 x 30 mm column, flow rate 100 ml/min, gradient 5-60% methanol in buffer (0.010 M aqueous ammonium acetate)] to give the title compound (0.0475 g, 0.100 mmol, 47% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.48 (d, J=8.8 Hz, 1H), 7.04-6.88 (m, 2H), 6.67 ( d, J=2.4 Hz, 1H), 4.10 (s, 2H), 3.54 (dt, J=10.4, 5.2 Hz, 1H), 3.41 (dt, J=9 .9, 7.3 Hz, 1H), 3.38-3.29 (m, 1H), 3.15 (dd, J=10.3, 3.7 Hz, 1H), 2.84 (s, 3H), 2.25 (dt, J=13.7, 6.8 Hz, 1H), 1.96-1.86 (m, 1H); MS (ESI ^- ) m/z 457 [MH] ^- .

Example 28: N -(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide (Compound 127)

Example 28A: N-(2-bromoethyl)cyclopropanesulfonamide

A mixture of 2-bromoethanamine hydrobromide (266 mg, 1.3 mmol), cyclopropanesulfonyl chloride (192 mg, 1.365 mmol) and triethylamine (395 mg, 3.90 mmol) in dichloromethane (10 ml) was stirred at room temperature for 4 hours. The mixture was diluted with dichloromethane (60 ml), washed with water (20 ml) and brine (20 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (200 mg 0.88 mmol, yield 67 %) as an oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.56 (t, J=8 Hz, 2H), 3.55 (m, 2H), 2.62 (m, 1H), 1 .01 (m, 4H).

Example 28B: N-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl ]hydroxy}ethyl)cyclopropanesulfonamide

A mixture of the product of example 1H (89 mg, 0.22 mmol), the product of example 28A (151 mg, 0.660 mmol) and cesium carbonate (215 mg, 0.660 mmol) in N,N -dimethylformamide (1 ml) was stirred at 75°C in within 2 hours. The solution was filtered. The residue was purified by silica gel flash column chromatography, eluting with dichloromethane then dichloromethane/methanol (10:1) to give the title compound (60 mg, 0.11 mmol, 50% yield) as a solid. MS (ESI ⁺ ) m/z 550 [M+1] ⁺ .

Example 28C: N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy }ethyl)cyclopropanesulfonamide

Trichloroborane (1201 μl, 1.201 mmol). The mixture was stirred at -78°C for 10 minutes and then at 0°C for 40 minutes. Ethanol (1 ml) was added at 0°C. The mixture was stirred for 20 minutes at room temperature and then concentrated under reduced pressure. The resulting solid was washed with heptane (5 mL×4), then dissolved in N,N -dimethylformamide (2.5 mL) and purified by preparative HPLC [YMC TriArt™ C18 hybrid 20 µm column, 25×150 mm, flow rate 80 ml/minute, 5-100% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide)] to give the title compound (10 mg, 0.022 mmol, 27% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.50 (s, 1H), 7.69 (d, J=8 Hz, 1H), 7.20 (d, J=2 Hz , 1H), 7.16 (dd, J=8, 2 Hz, 1H), 7.04 (s, 1H), 4.15 (t, J=8 Hz, 2H), 4.11 (s, 2H ), 3.41 (m, 2H), 2.63 (m, 1H), 0.94 (m, 4H); MS (ESI ^- ) m/z 458 [MH] ^- .

Example 29: 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione (Compound 128)

In a 4 ml tube with a septum screw cap were combined 3-amino-1-(methanesulfonyl)azetidine (0.065 g, 0.430 mmol), the product of example 1G (0.1 g, 0.215 mmol), sodium tert -butoxide (0.062 g, 0.645 mmol ), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 µmol) and BrettPhos (3.46 mg, 6.45 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (2 ml). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at room temperature, and then heated to 100°C. After 30 minutes at 100°C the reaction mixture was cooled to room temperature, then extinguished with 1 M hydrochloric acid (1 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×1 ml). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-1-fluoro-7- {[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 533 [MH] ^- .

To a suspension of the crude intermediate 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine -1,1,3-trione in dichloromethane (2.3 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (2.15 ml, 1 M, 2.15 mmol) along the wall of the flask so that the internal temperature remained below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 10°C before re-cooling to -78°C. The reaction was quenched by adding ethyl acetate (1 ml) followed by anhydrous ethanol (0.5 ml) and then warmed to room temperature and concentrated under reduced pressure to give a tan solid. The crude solid was suspended in heptanes (5 ml) and sonicated for 30 seconds to obtain a suspension. The solid was collected by filtration and washed with heptanes (2 ml). The solid was dissolved in dimethyl sulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [Waters XBridge™ C18 5 µm OBD column, 30 x 100 mm, flow rate 40 ml/min, gradient 3-30% methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 ammonium hydroxide)] to give the title compound (0.0357 g, 0.077 mmol, 36% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.51 (dd, J=9.0, 1.5 Hz, 1H), 6.96 (dd, J=8.9, 2 .3 Hz, 1H), 6.91 (s, 1H), 6.57 (d, J=2.4 Hz, 1H), 4.32 (dc, J=7.8, 5.8 Hz, 2H ), 4.23 (t, J=7.7 Hz, 3H), 4.09 (s, 2H), 3.00 (s, 3H); MS (ESI ^- ) m/z 443 [MH] ^- .

Example 30: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanonitrile ( Compound 129)

A mixture of the product of Example 1H (86 mg, 0.214 mmol), cesium carbonate (139 mg, 0.427 mmol) and 4-bromobutyronitrile (47.4 mg, 0.321 mmol) in N,N -dimethylformamide (1 mL) was stirred at ambient temperature for within 2 hours. In a separate tube, a mixture of the product of example 1H (86 mg, 0.214 mmol), cesium carbonate (139 mg, 0.427 mmol) and 4-bromobutyronitrile (47.4 mg, 0.321 mmol) in dioxane: N,N -dimethylformamide (2:1, 1.5 ml) was stirred at ambient temperature for 2 hours. The reaction mixtures were combined, diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4 -trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanonitrile, which was used in the next step without further purification. MS (CIAD ^- ) m/z 468 (MH) ^-

To a mixture of the above intermediate 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy }butanonitrile (200 mg, 0.426 mmol) and pentamethylbenzene (316 mg, 2.130 mmol) in dichloromethane (3 mL) a solution of boron trichloride (2.56 mL, 2.56 mmol) in dichloromethane was added dropwise at -78°C over 5 minutes. After 30 minutes the reaction was quenched with 2 N HCl (0.5 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was triturated with dichloromethane to give the title compound (90 mg, 0.237 mmol, 56%). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.35 (s, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.26-7.17 ( m, 2H), 7.08 (s, 1H), 4.49 (s, 2H), 4.15 (t, J=6.1 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.08 (n, J=6.6 Hz, 2H). MS (CIAD ^- ) m/z 378 [MH] ^- .

Example 31: [1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} methyl)cyclopropyl]acetonitrile (Compound 130)

Mixture of the product of Example 1H (150 mg, 0.373 mmol), cesium carbonate (243 mg, 0.746 mmol) and 2-(1-(bromomethyl)cyclopropyl)acetonitrile (97 mg, 0.559 mmol) in N,N -dimethylformamide (1.5 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate (60 ml) and water (15 ml) with 1.5 ml of 2N HCl. The ethyl acetate fraction was separated, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give [1-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo -1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl]acetonitrile, which was used in the next step without further purification. MS (CIAD ^- ) m/z 494 [MH] ^- .

To a mixture of the above intermediate [1-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl ]oxy}methyl)cyclopropyl]acetonitrile (185 mg, 0.373 mmol) and pentamethylbenzene (277 mg, 1.867 mmol) in dichloromethane (3 ml) at -78°C, a solution of boron trichloride (2.24 ml, 2.240 mmol) was added dropwise in dichloromethane for 5 minutes. After 30 minutes, the reaction was quenched with 2 ml of 0.5 N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was triturated with dichloromethane to give the title compound (85 mg, 0.210 mmol, 56% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.28 (s, 1H), 7.75-7.70 (m, 1H), 7.22 (m, 2H), 7, 07 (s, 1H), 4.45 (s, 2H), 4.00 (s, 2H), 2.80 (s, 2H), 0.77-0.70 (m, 2H), 0.72 -0.65 (m, 2H); MS (CIAD ^- ) m/z 404 [MH] ^- .

Example 32 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 131 )

Example 32A: 2-(dimethylamino)ethyl methanesulfonate

To a solution of 2-(dimethylamino)ethanol (500 mg, 5.61 mmol) in dichloromethane (25 ml) at 0°C were added methanesulfonyl chloride (0.523 ml, 6.73 mmol) and triethylamine (1.01 ml, 7.85 mmol ). The reaction mixture was stirred for 10 minutes at 0°C and 1 hour at room temperature. Water (5 ml) was then added and the mixture was extracted with dichloromethane. The organic layers were collected and washed with brine (2 ml) and dried over anhydrous Na ₂ SO ₄ . The volatiles were carefully removed under reduced pressure (bath temperature maintained at ~25°C) to give the title compound, which was subjected to the next reaction without purification.

Example 32B: 5-{3-(benzyloxy)-7-[2-(dimethylamino)ethoxy]-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione

To the product of Example 1H (150 mg, 0.373 mmol) in N,N -dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 32.8 mg, 0.820 mmol) in three portions at room temperature. The reaction was stirred for 30 minutes until the end of gas evolution. A solution of freshly prepared Example 32A (137 mg, 0.820 mmol) in N,N -dimethylformamide (2 ml) was slowly added to the reaction mixture. The reaction was stirred overnight at room temperature. Methanol (1 ml) was added, volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (91 mg, 0.192 mmol, 52% yield) as a white solid . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.55 (s, 1H), 7.81 (dd, J=9.1, 1.5 Hz, 1H), 7.60- 7.53 (m, 2H), 7.41-7.33 (m, 3H), 7.37-7.27 (m, 2H), 7.26 (dd, J=9.0, 2.5 Hz, 1H), 5.23 (s, 2H), 4.46 (t, J=5.0 Hz, 2H), 4.09 (s, 2H), 3.55 (t, J=5.0 Hz, 2H), 2.87 (s, 6H); MS (CIAD ^- ) m/z 472 [MH] ^- .

Example 32C: 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

The product from example 32B (88 mg, 0.186 mmol) and 1,2,3,4,5-pentamethylbenzene (83 mg, 0.558 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (5 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.56 ml, 0.558 mmol) in dichloromethane was added dropwise over 5 minutes. After 20 minutes, the reaction was quenched at -78°C with dichloromethane:ethanol=9:1 (1 ml), and then slowly warmed to room temperature. Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (30 mg, 0.078 mmol, 42% yield) as a white solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.53 (s, 1H), 7.71 (dd, J=9.0, 1.4 Hz, 1H), 7.28 ( d, J=2.6 Hz, 1H), 7.18 (dd, J=9.0, 2.6 Hz, 1H), 7.05 (s, 1H), 4.38 (t, J=5 .2 Hz, 2H), 4.10 (s, 2H), 2.75 (s, 6H); MS (CIAD ^- ) m/z 382 [MH] ^- .

Example 33: 5-{7-[1-(cyclopropylmethyl)-1 H -pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (Compound 132)

Example 33A: 5-{3-(benzyloxy)-7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione

To the product of example 1G (100 mg, 0.215 mmol) in dioxane (5 ml) was added 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1 H -pyrazole (80 mg, 0.322 mmol) and sodium carbonate (0.322 ml, 0.645 mmol). Tetrakis(triphenylphosphine)palladium (0) (24.8 mg, 0.021 mmol) was added and the reaction mixture was purged with N ₂ for 5 minutes. The mixture was heated at 100°C overnight. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was purified by column chromatography (SiO ₂ , dry load, 5% methanol in dichloromethane) to give the title compound (68 mg, 0.134 mmol, 63% yield). MS (CIAD-) m/z 505 [MH] ^- .

Example 33B: 5-{7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione

The product from Example 33A (50 mg, 0.099 mmol) and 1,2,3,4,5-pentamethylbenzene (43.9 mg, 0.296 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (5 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.296 ml, 0.296 mmol) in dichloromethane was added dropwise over 5 minutes. After 20 minutes, the reaction was quenched at -78°C with dichloromethane:ethanol=9:1 (1 ml), and then slowly warmed to room temperature. Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm) 30-100% gradient of acetonitrile (A) and 0.1 % ammonium acetate in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (18 mg, 0.043 mmol, 44% yield) as a white solid. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.71 (s, 1H), 8.34 (s, 1H), 8.00 (d, J=10.7 Hz, 2H) , 7.73 (s, 2H), 7.05 (s, 1H), 4.11 (s, 2H), 4.00 (d, J=7.1 Hz, 2H), 1.29 (tt, J=7.6, 4.8 Hz, 1H), 0.60-0.51 (m, 2H), 0.44-0.38 (m, 2H); MS (CIAD-) m/z 415 [MH] ^- .

Example 34 5-{1-Fluoro-3-hydroxy-7-[(1H-pyrazol-4-yl)methoxy]naphthalen-2-yl}-1 λ 6,2,5-thiadiazolidin- 1,1,3 -trione (Compound 133)

Example 34A: tert-butyl 4-((( methylsulfonyl )oxy)methyl)-1H-pyrazole-1-carboxylate

Methanesulfonyl chloride (202 mg, 1.760 mmol) in dichloromethane (1 ml) was added dropwise to a stirred cold (0°C) solution of tert -butyl 4-(hydroxymethyl)-1H - pyrazole-1-carboxylate (317 mg, 1.6 mmol) and triethylamine (324 mg, 3.20 mmol) in dichloromethane (6 ml). The reaction mixture was left to warm to ambient temperature and maintained at ambient temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 ml) and quenched with 0.2 N aqueous HCl (10 ml). The organic layer was separated and washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated to give the title compound (415 mg, 1.502 mmol, 94% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.44 (s, 1H), 7.91 (s, 1H), 5.21 (s, 2H), 2.32 (s, 3H), 1.58 (s, 9H).

Example 34B: tert-butyl 4-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl ]hydroxy}methyl)-1H-pyrazole-1-carboxylate

A mixture of the compound from example 1H (150 mg, 0.373 mmol), example 34A (206 mg, 0.746 mmol) and cesium carbonate (202 mg, 0.621 mmol) in N,N -dimethylformamide (1 ml) was stirred at 70°C for 40 minutes. The mixture was cooled to ambient temperature and diluted with ethyl acetate (50 ml). The organic phase was washed with 0.2 N aqueous HCl (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (215 mg, 0.369 mmol, 99% yield). MS (ESI ^- ) m/z 581 (MH) ^- .

Example 34C: 5-{1-Fluoro-3-hydroxy-7-[(1H-pyrazol-4-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione

Trichloroborane (2.832 ml, 2 .83 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 10 minutes, then at -20°C for 30 minutes. The mixture was quenched with ethanol (6 ml) and concentrated. The residue was washed with heptane (4×4 ml) and dichloromethane (6×3 ml) and concentrated to give the crude product. The crude product was dissolved in N,N -dimethylformamide (3 ml), filtered through a glass microfiber separator filter and purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 μm column, 50 x 100 mm, flow rate 140 ml/min, 5-55% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide)] to give the title compound (34 mg, 0.087 mmol, 33.7% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 12.85 (br s, 1H), 7.87 (br s, 1H), 7.66 (dd, J =8.2 Hz, 1H), 7.60 (br s, 1H), 7.29 (d, J = 2 Hz, 1H), 7.13 (dd, J = 8.2 Hz, 1H), 7.02 ( s, 1H), 5.08 (s, 2H), 4.11 (m, 1H), 4.09 (s, 2H); MS (ESI ^- ) m/z 391 (MH) ^- .

Example 35 5-[1-Fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 134)

Example 35A: 5-[3-(benzyloxy)-1-fluoro-7-(2-methylpropoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

1-iodo-2-methylpropane (0.09 ml, 0.77 mmol, 1.6 eq.) was added to a suspension of cesium carbonate (362 mg, 1.11 mmol, 2.2 eq.) and the product of Example 1H (201 mg, 0.5 mmol, 1 eq.) in N,N -dimethylformamide (1.0 ml) at 23°C. The reaction vessel (4 ml tube) was sealed and the sealed vessel was placed in a heating block that had been preheated to 60°C. The reaction mixture was stirred for 2 hours at 60°C. The reaction mixture was cooled to 23°C for 5 minutes. Added additional amount of 1-iodo-2-methylpropane (0.09 ml, 0.77 mmol, 1.6 eq.) at 23°C. The reaction vessel was sealed and the sealed vessel was placed in the heating block, which was preheated to 100°C. The reaction mixture was stirred for 3 hours at 100°C. The reaction mixture was cooled to 23°C for 5 minutes. Added additional amount of 1-iodo-2-methylpropane (0.09 ml, 0.77 mmol, 1.6 eq.) at 23°C. The reaction vessel was sealed and the sealed vessel was placed in the heating block, which was preheated to 100°C. The reaction mixture was stirred for 1 hour at 100°C. The product mixture was cooled to 23° C. over 15 minutes. The cooled mixture was diluted with water (0.5 ml) and dimethyl sulfoxide (5.0 ml). The diluted mixture was purified by reverse phase flash column chromatography (100 g RediSep® Gold C18 column, eluting with a gradient of 10-100% [v/v] methanol - 0.025 M aqueous ammonium bicarbonate [acidified with solid carbon dioxide], 10 column volumes followed by isocratic elution with 100% methanol, 3 column volumes, flow rate=60 ml/minute) to give the title compound as a yellow solid (59.0 mg, 25%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.77 (dd, J =9.6, 4.0 Hz, 1H), 7.49-7.32 (m, 6H), 7.23-7.17(m, 2H), 5.17(d, J =17.4Hz, 2H), 7.73(s, 1H), 4.66(s, 1H), 3.93 (d, J =6.7 Hz, 1H), 3.27 (d, J =7.6 Hz, 1H), 1.88 (dc, J =13.4, 6.7 Hz, 1H), 0 .86 (d, J =6.7 Hz, 2H), 0.79 (d, J =6.7 Hz, 2H); MS (CIAD ⁺ ) m / z 459 [M+H] ⁺ .

Example 35B: 5-[1-Fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A solution of boron trichloride in dichloromethane (1.0 M, 0.80 mL, 0.80 mmol, 6.2 eq) was added to a suspension of the product of Example 35A (59.0 mg, 0.13 mmol, 1 eq) in dichloromethane (1.5 ml) at -78°C. The reaction mixture was stirred for 10 minutes at -78° C. (dry ice/acetone bath). The reaction vessel was then transferred to an ice bath. The reaction mixture was stirred for 10 minutes at 0°C. The reaction vessel was then returned to the dry ice/acetone bath. The reaction mixture was stirred for 5 minutes at -78°C. The product mixture was then slowly diluted with ethanol (2.0 ml) at -78°C. The diluted mixture was heated to 23°C and the heated mixture was concentrated. The resulting residue was triturated with heptanes (5 ml). The resulting residue was dissolved in 10% acetone-dichloromethane (2.0 ml) and the solution was diluted with heptanes (10.0 ml). A precipitate formed and the mother liquor was decanted. The resulting residue was triturated with heptanes (1.0 ml) to give the compound (10.2 mg, 22%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.65 (dd, J =11.9, 9.2 Hz, 1H), 7.14-7.09 (m, 2H), 7.03 (d, J = 13.4 Hz, 1H), 4.80 (s, 1H), 4.63 (s, 1H), 4.26 (d, J = 6.6 Hz, 1H), 3.43 (d, J = 7.6 Hz, 1H), 2.13-2.04 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.94 (d , J =6.7 Hz, 3H); MS (CIAD ⁺ ) m / z 369 [M+H] ⁺ .

Example 36 5-[1-Fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 135)

Example 36A: 5-[3-(Benzyloxy)-1-fluoro-7-(2-hydroxypropoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from Example 1H (120 mg, 0.298 mmol) in N,N -dimethylformamide (2 mL) was added cesium carbonate (214 mg, 0.656 mmol) and 1-bromo-2-propanol (41.4 mg, 0.298 mmol ). The mixture was heated to 80° C. overnight. After cooling, the mixture was filtered by passing through diatomaceous earth, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (30 mg, 0.065 mmol, 22% yield) . MS (CIAD ^- ) m/z 459 [MH] ^- .

Example 36B: 5 - [1 - fluoro - 3 - hydroxy - 7 - (2 - hydroxypropoxy)naphthalene - 2 - yl] - 1 λ ⁶ ,2,5 - thiadiazolidin - 1,1,3 - trione

The product from Example 36A (30 mg, 0.065 mmol) and tetrahydrofuran (3 mL) were added in 10% Pd(OH) ₂ /C (wet, 60 mg, 0.214 mmol) to a 20 mL Barnstead Hast C reactor with a glass liner and the mixture stirred. at 25°C for 21.1 hours at 113 psi. inch of hydrogen. The mixture was filtered through a pad of diatomaceous earth, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A ) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (6 mg, 0.016 mmol, 25% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.31 (s, 1H), 7.75-7.68 (m, 1H), 7.27-7.18 (m, 1H ), 7.19 (s, 1H), 7.07 (s, 1H), 4.48 (s, 2H), 4.00 (n, J = 5.9 Hz, 1H), 3.99-3 .86 (m, 2H), 1.19 (d, J = 6.3 Hz, 3H); MS (CIAD ^- ) m/z 369 [MH] ^- .

Example 37 N- (cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide (Compound 136 )

Example 37A: methyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxylate

To a mixture of the compound from Example 1G (2.5 g, 5.37 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.079 g, 0.107 mmol) in a 50 mL stainless steel pressure reactor methanol (25 ml) and triethylamine (1.498 ml, 10.75 mmol) were added. The reactor was degassed several times with nitrogen gas, followed by refilling with carbon monoxide gas to 60 psi. inch. The mixture was heated to 80° C. and stirred for 10 hours at 60 psi. inch of carbon monoxide. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , 5% methanol in dichloromethane) to give the title compound (1.5 g, 3.38 mmol, 63% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.97 (s, 3H), 8.55 (d, J =1.6 Hz, 1H), 8.05-7.91 ( m, 2H), 7.60-7.55 (m, 2H), 7.47 (s, 1H), 7.42-7.28 (m, 3H), 5.31 (s, 2H), 4 .10 (s, 2H), 3.92 (s, 3H); MS (CIAD ^- ) m/z 443 [MH] ^- .

Example 37B: 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxylic acid

To a solution of the compound from example 37A (200 mg, 0.450 mmol) in methanol (1 ml), tetrahydrofuran (1 ml) and water (1 ml) was added LiOH (32.3 mg, 1.350 mmol) at ambient temperature, and the mixture was stirred overnight at ambient temperature. The pH of the reaction mixture was adjusted to neutral by adding HCl (2 N). The mixture was extracted with ethyl acetate (3×3 ml), the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (150 mg, 0.349 mmol, 77% yield) . MS (CIAD ^- ) m/z 429 [MH] ^- .

Example 37C: N-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide

To a solution of the compound from Example 37B (150 mg, 0.349 mmol) in N,N -dimethylformamide (2 mL) was added cyclopropylmethanamine (49.6 mg, 0.697 mmol), (1-[bis(dimethylamino)methylene]-1 H -1 ,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (139 mg, 0.366 mmol) and triethylamine (106 mg, 1.046 mmol) and the mixture was stirred at 60° C. overnight After cooling, water ( 10 ml) and the mixture was extracted with ethyl acetate (3×5 ml) The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give 6-(benzyloxy) -N- (cyclopropylmethyl)-8-fluoro-7-(1, 1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide, which was carried to the next step without purification MS (APCI ^- ) m/z 482 [MH] ^- .

6-(benzyloxy)- N -(cyclopropylmethyl)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide and tetrahydrofuran (2 ml ) was added in 5% Pd/C (120 mg, 0.525 mmol) in a 20 ml Barnstead reactor with a glass liner. The mixture was stirred at 25° C. for 18 hours under 50 psi conditions. inch of hydrogen. The mixture was filtered, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0 1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (46 mg, 0.117 mmol, 47% yield over two steps). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.96 (s, 1H), 8.78 (t, J =5.7 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H), 7.96 (dd, J =8.7, 1.8 Hz, 1H), 7.85 (dd, J =8.8, 1.4 Hz, 1H), 7, 16 (s, 1H), 4.52 (s, 2H), 3.19 (dd, J =6.8, 5.7 Hz, 2H), 1.12-1.01 (m, 1H), 0 .49-0.40 (m, 2H), 0.29-0.22 (m, 2H); MS (CIAD-) m/z 392 [MH] ^-

Example 38: 5-[1-fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione (Compound 137)

The title compound was prepared using the procedures described in Example 46 replacing 2-(trifluoromethoxy)ethanamine with propane-2-amine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.56 (s, 1H), 8.71 (br s, 2H), 7.73 (d, J =8, Hz, 1H ), 7.26 (d, J =2, Hz, 1H), 7.20 (dd, J =8.2 Hz, 1H), 7.05 (s, 1H), 4.37 (m, 4H) , 4.11 (t, J =6 Hz, 2H), 4.10 (s, 2H), 3.42 (m, 2H); MS (ESI ^- ) m/z 466 (MH) ^- .

Example 39: 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ^1,1 , 3-trione (Compound 138)

The title compound was prepared using the procedures described in Example 46 replacing 2-methoxyethanamine with propane-2-amine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.51 (s, 1H), 8.25 (br s, 2H), 7.72 (d, J =8, Hz, 1H ), 7.25 (d, J =2, Hz, 1H), 7.19 (dd, J =8.2 Hz, 1H), 7.05 (s, 1H), 4.32 (t, J = 6 Hz, 2H), 4.09 (s, 2H), 3.59 (t, J =6 Hz, 2H), 3.35 (m, 2H), 3.29 (s, 3H), 3.17 (m, 2H); MS (ESI ^- ) m/z 412 (MH) ^- ; MS (ESI ^- ) m/z 366 (MH) ^- .

Example 40 5-{1-Fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione (Compound 139)

The title compound was prepared using the procedures described in Example 41, replacing the methanamine with ethanamine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.44 (s, 1H), 8.51 (br s, 2H), 7.74 (d, J =8, Hz, 1H ), 7.73 (d, J =2, Hz, 1H), 7.40 (dd, J =8.2 Hz, 1H), 7.10 (s, 1H), 4.42 (s, 2H) , 2.87 (m, 2H), 2.81 (t, J =7, Hz, 2H), 2.54 (m, 3H), 1.96 (m, 2H).

Example 41 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 140 )

Example 41A: 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]propanal

A mixture of the compound from Example 1G (0.60 g, 1.290 mmol), 2-(di - tert - butylphosphino ) biphenyl (0.058 g, 0.193 mmol), palladium(II) acetate (0.043 g, 0.193 mmol), prop-2- en-1-ol (0.225 g, 3.87 mmol) and triethylamine (0.261 g, 2.58 mmol) in N,N -dimethylformamide (4 mL) were placed under a nitrogen atmosphere and heated to 120°C for 1.5 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate (60 ml). The organic phase was washed with 0.5 N aqueous HCl (10 ml) and brine (10 ml × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (520 mg, 1.175 mmol, 92% yield) . MS (ESI ^- ) m/z 441 (MH) ^- .

Example 41B: 5-{3-(benzyloxy)-7-[3-(ethylamino)propyl]-1-fluoronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A mixture of the compound from Example 41A (100 mg, 0.226 mmol), triethylamine (114 mg, 1.130 mmol), ethanamine (0.339 mL, 0.678 mmol) and sodium triacetoxyborohydride (192 mg, 0.904 mmol) in acetonitrile/methanol (4:1, 3 ml) was stirred at ambient temperature for 18 hours. After that, methanol/water (1:2, 2 ml) was added. The solution was filtered and the filtrate was purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 μm column, 50 x 100 mm, flow rate 140 ml/min, 5-70% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound (35 mg, 0.074 mmol, 32.8% yield). MS (ESI ^- ) m/z 470 (MH) ^- .

Example 41C: 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Trichloroborane (0.816 ml , 0.816 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 10 minutes, then at -20°C for 20 minutes. The mixture was quenched with ethanol (3 ml) and concentrated. The residue was washed with heptane (4×4 ml) and dichloromethane (6×3 ml) and concentrated to give the title compound (27 mg, 0.071 mmol, 95% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.51 (s, 1H), 8.63 (br s, 2H), 7.74 (d, J =8, Hz, 1H ), 7.73 (d, J =2, Hz, 1H), 7.42 (dd, J =8.2 Hz, 1H), 7.11 (s, 1H), 4.45 (s, 2H) , 2.90 (m, 4H), 2.82 (t, J =7, Hz, 2H), 1.98 (m, 2H), 1.17 (t, J =7 Hz, 3H); MS (ESI ^- ) m/z 380 (MH) ^- .

Example 42: 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trione (Compound 141)

Example 42A: (5 - bromothiophene - 2 - yl) (dimethyl) oxo -λ ⁵ - phosphate

Tris(dibenzylideneacetone)dipalladium (0) (Pd ₂ (dba) ₃ , 11.73 mg, 0.013 mmol) and (9,9-dimethyl-9 H -xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos, 14.83 mg, 0.026 mmol) at 20°C under nitrogen atmosphere. Then the reaction mixture was stirred for 12 hours at 20°C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC [Agela-SNAP 20-35 µm flash column, 100 Å C18, 120 g, flow rate 20 ml/min, control wavelength: 220 and 254 nm, 0-35% gradient of acetonitrile in water] to give the title compound (220 mg, 0.874 mmol, 68.2% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.32 (dd, J =7.88, 3.75 Hz, 1H), 7.13-7.16 (m, 1H), 1, 79 (d, J =13.26 Hz, 6H).

Example 42B: 5 - [3 - (benzyloxy) - 1 - fluoro - 7 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolane - 2 - yl)naphthalene - 2 - yl] - 1 λ ^6,2,5 - thiadiazolidin - 1,1,3 - trione and [6 - (benzyloxy) - 8 - fluoro - 7 - (1,1,4 - trioxo - 1 λ ^6,2,5 - thiadiazolidine - 2 - yl)naphthalene - 2 -yl ]boronic acid

[ 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct, 140 mg, 0.172 mmol) at 20°C under nitrogen atmosphere. Then the reaction mixture was stirred for 4 hours at 80°C. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC [Agela-SNAP C18 flash column 20～35 µm, 100 Å, 120 g, flow rate 120 ml/min, 0-45% gradient of acetonitrile in water, control wavelength: 220 and 254 nm] and concentrated the solution under reduced pressure to give a mixture of the title compounds (300 mg, 0.577 mmol, 67.1% yield). ¹ H NMR (400 MHz, DMSO- d6 ₎ δ ppm 8.50 (s, 1H), 8.30 (s, 1H), 7.95 (d, J =8.25 Hz, 1H) , 7.85-7.89 (m, 1H), 7.78-7.84 (m, 2H), 7.53 (bd, J =7.38 Hz, 4H), 7.30-7 .44 (m, 8H), 5.29 (br s, 4H), 4.50 (br d, J =6.50 Hz, 4H), 1.34 (s, 9H), 1.15- 1.17 (m, 3H).

Example 42C: 5-{3-(benzyloxy)-7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5 ^- thiadiazolidin-1,1, 3-trione

Tetrakis[triphenylphosphine]palladium (0) (Pd(Ph ₃ P) ₄ , 17.40 mg, 0.015 mmol) was added to a mixture of compounds from Example 42B (86 mg, 0.181 mmol), sodium carbonate (Na ₂ CO ₃ , 31, 9 mg, 0.301 mmol) and the compound from example 42A (40 mg, 0.151 mmol) in toluene (2 ml), ethanol (1 ml) and water (0.5 ml) under nitrogen at 20°C. The mixture was stirred for 2 hours at 100° C. under nitrogen. The mixture was then cooled to 25°C. One additional 10 mg tube and one additional 40 mg tube were prepared as described above. These three reactions were combined and diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (3 x 20 ml). The aqueous solution was acidified with aqueous 1 M hydrochloric acid to pH=3. The resulting mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [5 μm column Welch Xtimate™ C18 150×25 mm, flow rate 25 ml/minute, 30-50% gradient over 15 minutes of acetonitrile in aqueous ammonium bicarbonate (10 mM), wavelength: 220 and 254 nm]. The resulting solution was acidified with aqueous 1 M hydrochloric acid to pH=3 and extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (40 mg, 0.070 mmol, 20.60% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.97 (s, 2H), 7.82 (dd, J= 3.69, 1.69 Hz, 1H), 7.63 ( dd, J= 7.13, 3.75 Hz, 1H), 7.47-7.58 (m, 3H), 7.30-7.44 (m, 3H), 5.30 (s, 2H) , 4.49 (s, 2H), 1.78 (d, J= 13.76 Hz, 6H); MS (ESI ^- ) m / z 543 (MH) ^- .

Example 42D: 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trione, ammonium salt

Trichloroborane (0.366 ml, 0.366 mmol) was added dropwise to a mixture of the compound from Example 42C (35 mg, 0.061 mmol) in anhydrous dichloromethane (10 mL) at 0°C. Then the reaction mixture was stirred for 2 hours at 20°C. One additional 5 mg tube was prepared as described above. The two reaction mixtures were combined, quenched with 5 ml of methanol and concentrated under reduced pressure. The residue was dissolved in N,N -dimethylformamide and purified by preparative HPLC [Gilson 281 semi-preparative HPLC system, Welch Xtimate™ C18 column, 150×25 mm, 5 µm, flow rate 25 ml/min, 30-50% acetonitrile gradient in buffer (10 mM aqueous ammonium bicarbonate), wavelength: 220 and 254 nm] and lyophilized to give the title compound (15 mg, 0.030 mmol, 43.2% yield) as ammonium salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.13 (s, 1H), 7.83 (s, 2H), 7.77 (dd, J =3.50, 1.50 Hz, 1H), 7.61 (dd, J = 7.07, 3.69 Hz, 1H), 7.34-7.56 (m, 3H), 7.10 (s, 1H), 4.11 (s, 2H), 1.77 (d, J =13.76 Hz, 6H); MS (ESI ^- ) m / z 453 (MH) ^- .

Example 43 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 142 )

The title compound was prepared using the procedures described in Example 46, replacing cyclopropanamide with propane-2-amine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.99 (s, 1H), 8.95 (br s, 2H), 7.75 (d, J =8, Hz, 1H ), 7.29 (d, J =2, Hz, 1H), 7.27 (dd, J =8.2 Hz, 1H), 7.09 (s, 1H), 4.38 (t, J = 5 Hz, 2H), 4.30 (s, 2H), 3.49 (m, 2H), 2.83 (m, 1H), 0.87 (m, 2H), 0.79 (m, 2H) ; MS (ESI ^- ) m/z 394 (MH) ^- .

Example 44 5-{1-Fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione (Compound 143)

The title compound was prepared using the procedures described in Example 46, replacing the methanamine with propane-2-amine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.16 (br s, 1H), 8.72 (br s, 2H), 7.72 (d, J =8, Hz , 1H), 7.25 (d, J =2, Hz, 1H), 7.21 (dd, J =8, 2 Hz, 1H), 7.05 (s, 1H), 4.34 (s, 2H), 4.32 (t, J =5 Hz, 2H), 3.47 (m, 2H), 2.62 (m, 3H); MS (ESI ^- ) m/z 368 (MH) ^- .

Example 45 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 144 )

The title compound was prepared using the procedures described in Example 46, replacing ethanamine with propane-2-amine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.81 (s, 1H), 8.93 (br s, 2H), 7.74 (d, J =8, Hz, 1H ), 7.37 (d, J =2, Hz, 1H), 7.24 (dd, J =8.2 Hz, 1H), 7.07 (s, 1H), 4.52 (t, J = 5 Hz, 2H), 4.21 (s, 2H), 3.45 (m, 2H), 3.06 (m, 2H), 1.23 (t, J =7 Hz, 3H); MS (ESI ^- ) m/z 382 (MH) ^- .

Example 46: 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione (Compound 145)

Example 46A: 5-[3-(Benzyloxy)-7-(2,2-dimethoxyethoxy)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A mixture of the compound from example 1H (520 mg, 1.292 mmol), cesium carbonate (1011 mg, 3.10 mmol) and 2-bromo-1,1-dimethoxyethane (437 mg, 2.58 mmol) in N,N -dimethylformamide ( 3 ml) was stirred at 70°C for 4 hours. The reaction was cooled to ambient temperature and quenched with 0.2 N aqueous HCl (20 ml). The mixture was extracted with ethyl acetate (60 ml x 2). The combined organic phases were washed with brine (10 ml x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (120 g), eluted with ethyl acetate followed by ethyl acetate/methanol (10:1) to give the title compound (485 mg, 0.989 mmol, 77% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.77 (d, J =8 Hz, 1H), 7.56 (d, J =8 Hz, 2H), 7.37 (t , J = 8 Hz, 2H), 7.32 (m, 2H), 7.29 (d, J = 2 Hz, 1H), 7.23 (dd, J = 8.2 Hz, 1H), 5, 22 (s, 2H), 4.75 (t, J =6 Hz, 1H), 4.12 (s, 2H), 4.11 (d, J =6 Hz, 2H), 3.38 (s, 6H); MS (ESI ^- ) m/z 489 (MH) ^- .

Example 46B: {[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetaldehyde

A mixture of the compound from Example 46A (123 mg, 0.251 mmol) in hydrogen chloride (0.125 ml, 0.50 mmol, 4 N in dioxane) and water (0.05 ml) was stirred at ambient temperature for 15 minutes. The mixture was diluted with ethyl acetate (70 ml). The organic phase was washed with water (15 ml x 3) and brine (15 ml), dried over sodium sulfate, filtered and concentrated to give the title compound (112 mg, 0.252 mmol, 100% yield). MS (ESI ^- ) m/z 443 (MH) ^- .

Example 46C: 5-[3-(Benzyloxy)-1-fluoro-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl]-1 λ 6 ,2,5 ^- thiadiazolidin- 1,1,3-trione

Mixture of the compound from Example 46B (111 mg, 0.250 mmol), triethylamine (126 mg, 1.249 mmol), propane-2-amine (44.3 mg, 0.749 mmol) and sodium triacetoxyborohydride (212 mg, 0.999 mmol) in acetonitrile/methanol (4:1, 3 ml) was stirred at ambient temperature for 18 hours. After that, methanol/water (1:2, 2 ml) was added. The solution was filtered and the filtrate was purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 μm column, 50 x 100 mm, flow rate 140 ml/min, 5-55% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound (68 mg, 0.139 mmol, 55.8% yield). MS (ESI ^- ) m/z 486 (MH) ^- .

Example 46D: 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione

Trichloroborane (1.498 ml , 1.498 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 10 minutes, then at -20°C for 30 minutes. The mixture was quenched with ethanol (3 ml) and concentrated. The residue was washed with heptane (4×4 ml) and dichloromethane (4×3 ml) and concentrated to give the title compound (48 mg, 0.121 mmol, 97% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.61 (s, 1H), 9.00 (br s, 2H), 7.72 (d, J =8, Hz, 1H ), 7.25 (d, J =2, Hz, 1H), 7.21 (dd, J =8.2 Hz, 1H), 7.07 (s, 1H), 4.39 (t, J = 5 Hz, 2H), 4.09 (s, 2H), 3.37 (m, 1H), 2.52 (m, 2H), 1.29 (d, J =7 Hz, 6H); MS (ESI ^- ) m/z 396 (MH) ^- .

Example 47 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3-trione (Compound 146 )

Example 47A: 3-(diethylphosphoryl)propan-1-ol

Diethyl-λ ⁵ -phosphanone (2 g, 18.28 mmol) with stirring for 40 minutes at 100° C. under nitrogen. The mixture was stirred for 3 hours at 100°C. Thin layer chromatography (I ₂ , ethyl acetate:methanol=5:1, _Rf =0.3) indicated that the starting material had been consumed. The mixture was then purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (0-100%) and methanol/ethyl acetate (0-10%) to give the title compound (1.9 g, 53.8% yield). . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.72 (t, J =5.29 Hz, 2H), 1.67-1.99 (m, 8H), 1.10-1, 24 (m, 6H).

Example 47B: 3-(diethylphosphoryl)propyl methanesulfonate

To a solution of the compound from Example 47A (2.9 g, 15.01 mmol) in dichloromethane (100 ml) was added triethylamine (4.19 ml, 30.0 mmol) followed by dropwise addition of methanesulfonyl chloride (1.404 ml, 18. 02 mmol) at 0°C under nitrogen atmosphere. The mixture was then stirred for 1 hour at 0°C. Thin layer chromatography (I ₂ , ethyl acetate:methanol=3:1, _Rf =0.25) indicated that the starting material had been consumed. The mixture was then quenched with water (250 ml) and the resulting mixture was extracted with dichloromethane (3×150 ml). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.8 g, 42.1% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.30-4.36 (m, 2H), 3.04 (s, 3H), 2.04-2.15 (m, 2H), 1.68-1.84 (m, 7H), 1.12-1.24 (m, 7H).

Example 47C: 5-{3-(benzyloxy)-7-[3-(diethylphosphoryl)propoxy]-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione

To a solution of the compound from example 1H (515 mg, 2.125 mmol) in N,N -dimethylformamide (4 ml) were added in order cesium carbonate (Cs ₂ CO ₃ , 462 mg, 1.417 mmol) and the compound from example 47B (515 mg, 2.125 mmol) at 20°C. Then the reaction mixture was stirred for 4 hours at 80°C. The mixture was quenched with water (50 ml) and the mixture was acidified by dropwise addition of aqueous 1 M hydrochloric acid to pH=3. The resulting mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic phases were washed with brine (3 x 30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (350 mg, 77% yield), which was used in the next step without further purification. MS (ESI ^- ) m / z 547 (MH) ^- .

Example 47D: 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3-trione, ammonium salt

To a solution of the compound from Example 47C (350 mg, 0.542 mmol) in N,N -dimethylformamide (1 mL) and tetrahydrofuran (30 mL) was added 10% Pd/C (500 mg, 2.349 mmol) at 20° C. under argon. The reaction mixture was then stirred for 2 hours at 20° C. under balloon hydrogen (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure to remove most of the tetrahydrofuran. The resulting solution was purified by preparative HPLC [Shimadzu LC-8A, Waters Xbridge™ BEH C18 100×25 mm, 5 µm column, flow rate 30 ml/min, 2-30% acetonitrile gradient in buffer (10 mM aqueous ammonium bicarbonate , wavelength: 220 and 254 nm)] and lyophilized to give the title compound as ammonium salt (53 mg, 20.00% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.21-9.64 (m, 1H), 7.66 (d, J =8.88 Hz, 1H), 7.00- 7.20 (m, 6H), 4.12 (t, J =6.25 Hz, 2H), 4.08 (s, 2H), 1.89-2.00 (m, 2H), 1.74 -1.84 (m, 2H), 1.65 (dc, J =11.88, 7.67 Hz, 4H), 0.98-1.07 (m, 6H); ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ ppm 7.67 (d, J =8.88 Hz, 1H), 7.11-7.20 (m, 2H), 4.13 (t, J =6.25 Hz, 2H), 4.09 (s, 2H), 1.88-1.99 (m, 2H), 1.75-1.85 (m, 2H) , 1.66 (dc, J =11.90, 7.71 Hz, 4H), 0.98-1.09 (m, 6H); MS (ESI ^- ) m / z 547 (MH) ^- .

Example 48 5-{1-Fluoro-3-hydroxy-7-[(3 S )-3-hydroxybutoxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 147)

The title compound was prepared using the procedures described in Example 50 replacing ( S )-butane-1,3-diol with ( R )-butane-1,3-diol. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.36 (br s, 1H), 7.66 (dd, J = 8.2 Hz, 1H), 7.24 (br s, 1H), 7.24 (br s, 1H), s, 3H), 7.17 (d, J =2 Hz, 1H), 7.12 (dd, J =8, 2 Hz, 1H), 7.02 (s, 1H), 4.59 (d, J = 5 Hz, 1H), 4.13 (m, 2H), 4.09 (s, 2H), 3.85 (m, 1H), 1.81 (m, 2H), 1.14 (d, J = 7 Hz, 3H); MS (ESI ^- ) m/z 383 (MH) ^- .

Example 49 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3-trione (Compound 148)

To a solution of the product of Example 1G (1.000 g, 2.149 mmol) in dimethylformamide (20 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.523 g, 4.30 mmol ) followed by heating the resulting solution to 60°C. After 3 hours another part of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (0.381 g, 1.075 mmol) was added with continued heating. After 2.5 hours the reaction mixture was cooled to room temperature, quenched with 1 M aqueous sodium thiosulfate (50 ml) and acidified to pH < 4 with concentrated hydrochloric acid. The crude aqueous layer was extracted with ethyl acetate (3×50 ml). The organic layers were combined and washed successively with saturated aqueous ammonium chloride (2×50 ml) and then with a 6:1 mixture of brine and 2 M hydrochloric acid (30 ml). The organic layer was dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 483 [MH] ^- .

5-[3-(Benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (0 .5012 g, 1.037 mmol), cesium carbonate (1.014 g, 3.11 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1 '-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (BrettPhos Pd G3 precatalyst, 0.028 g, 0.031 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2 ',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 0.017 g, 0.031 mmol). The solids were placed under vacuum for 5 minutes at ambient temperature, then the tube was filled with nitrogen followed by tert -amyl alcohol (10 mL) and isoamylamine (0.241 mL, 2.074 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 33 hours the reaction mixture was cooled to ambient temperature, then extinguished with 1 M hydrochloric acid (5 ml) and diluted with ethyl acetate (5 ml). The aqueous layer was extracted with ethyl acetate (2×5 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (2.5 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-1,4- difluoro-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (APCI ⁺ ) m/z 490 [M+H] ⁺ .

To a suspension of crude 5-{3-(benzyloxy)-1,4-difluoro-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione (0.508 g, 1.038 mmol) and pentamethylbenzene (0.308 g, 2.075 mmol) in dichloromethane (10 ml) at -78°C, a solution of boron trichloride in dichloromethane (7.8 ml, 1 M, 7.8 mmol) was slowly added along walls of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (5 ml) followed by anhydrous ethanol (5 ml). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 5 ml) followed by acetonitrile (3 x 5 ml) and methanol (3 x 5 ml) to give the title compound (0.0056 g, 0.014 mmol, yield 1, 4%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.12 (s, 1H), 7.68 (dd, J =9.0, 1.6 Hz, 1H), 7.18 ( dd, J =9.2, 2.2 Hz, 1H), 6.75 (s, 1H), 4.49 (s, 2H), 3.12 (t, J =7.3 Hz, 2H), 1.80-1.65 (m, 1H), 1.51 (k, J =7.1 Hz, 2H), 0.93 (d, J =6.6 Hz, 6H); MS (APC ⁺ ) m/z 400 [M+H] ⁺ .

Example 50: 5-{1-Fluoro-3-hydroxy-7-[(3 R )-3-hydroxybutoxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 149)

Example 50A: (R)-3-hydroxybutyl methanesulfonate

To a mixture of ( R )-butane-1,3-diol (160 mg, 1.78 mmol) and triethylamine (270 mg, 2.67 mmol) in dichloromethane (3 ml) at 0°C was added methanesulfonyl chloride (214 mg, 1.869 mmol) in dichloromethane (1 ml). The mixture was stirred at 0°C for 1 hour and then at ambient temperature for 1 hour. The mixture was diluted with dichloromethane (40 ml) and washed with 0.1 N aqueous HCl (10 ml) and water (10 ml). The organic phase was dried over sodium sulfate, filtered and concentrated to give the title compound (275 mg, 1.635 mmol, 92% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.63 (d, J =6 Hz, 1H), 4.27 (m, 2H), 3.72 (m, 1H), 3 .15 (s, 3H), 1.71 (m, 2H), 1.05 (d, J =7 Hz, 3H).

Example 50B: 5-{3-(benzyloxy)-1-fluoro-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3- trion

A mixture of the compound from Example 1H (130 mg, 0.323 mmol), Example 50A (272 mg, 1.615 mmol) and cesium carbonate (421 mg, 1.292 mmol) in N,N -dimethylformamide (1 mL) was stirred at 65°C for 0 .5 hours. The mixture was quenched with aqueous 0.2 N HCl (15 ml) and extracted with ethyl acetate (80 ml). The organic phase was washed with brine (15 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 µm column, 50 x 100 mm, flow rate 140 ml/min, 5-60% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide) ] to give the title compound (80 mg, 0.169 mmol, 52.2% yield). MS (ESI ^- ) m/z 473 (MH) ^- .

Example 50C: 5-{1-Fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3-trione

Trichloroborane (1.322 ml , 1.322 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 20 minutes and then at -20°C for 20 minutes. The mixture was quenched with ethanol (3 ml) and concentrated. The residue was washed with heptane (4×4 ml) and concentrated to give the crude product. The crude material was purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 µm column, 50×100 mm, flow rate 140 ml/min, 5-50% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide )] to give the title compound (36 mg, 0.09 mmol, 67.8% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.66 (dd, J =8.2 Hz, 1H), 7.24 (br s, 4H), 7.17 (d, J =2Hz, 1H), 7.12(dd, J =8.2Hz, 1H), 7.02(s, 1H), 4.59(d, J =5Hz, 1H), 4.13 (m, 2H), 4.09 (s, 2H), 3.85 (m, 1H), 1.81 (m, 2H), 1.14 (d, J =7 Hz, 3H); MS (ESI ^- ) m/z 383 (MH) ^- .

Example 51 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 150)

Example 51A: 5-[3-(benzyloxy)-7-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylethoxy)-1-fluoronaphthalen-2-yl]-1 λ 6 ^.2 , 5-thiadiazolidin-1,1,3-trione

A solution of 2-bromo-1-cyclopropylethanol (250 mg, 1.515 mmol) in dichloromethane (2 ml) was added to a stirred solution of tert -butyldimethylchlorosilane (240 mg, 1.591 mmol) and imidazole (113 mg, 1.666 mmol) in dichloromethane (2 ml) . The mixture was stirred at ambient temperature for 3 hours. Water (5 ml) was added and the mixture was extracted with dichloromethane (3×5 ml). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. (2-bromo-1-cyclopropylethoxy)( tert -butyl)dimethylsilane was carried to the next step without purification.

To a solution of the compound from Example 1H (120 mg, 0.298 mmol) in N,N -dimethylformamide (2 mL) was added cesium carbonate (214 mg, 0.656 mmol) and crude (2-bromo-1-cyclopropylethoxy)( tert -butyl) dimethylsilane (167 mg, 0.596 mmol). The mixture was heated to 80° C. overnight. After cooling, the volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (64 mg, 0.107 mmol, 36% yield) . MS (CIAD ^- ) m/z 599 [MH] ^- .

Example 51B: 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A 250 ml round bottom flask was filled with nitrogen followed by the addition of Pd/C (4.34 mg, 0.041 mmol) and tetrahydrofuran (8 ml). A solution of the compound from Example 51A (100 mg, 0.166 mmol) in tetrahydrofuran (2 ml) was then added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. The volatiles were removed under reduced pressure, and the crude 5-[7-(2-{[ tert -butyl(dimethyl)silyl]oxy}-2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione was carried to the next step without purification. MS (CIAD ^- ) m/z 509 [MH] ^-

To a solution of crude 5-[7-(2-{[ tert -butyl(dimethyl)silyl]oxy}-2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidine -1,1,3-trione (100 mg, 0.196 mmol) in 1,4-dioxane (3 ml) was added 4 M HCl in dioxane (4 ml) and the reaction mixture was stirred at ambient temperature for 6 hours. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.37 (s, 1H), 7.76-7.68 (m, 1H), 7.24-7.17 (m, 2H ), 7.07 (d, J =1.3 Hz, 1H), 4.52 (s, 2H), 4.09 (dd, J =9.9, 4.1 Hz, 1H), 4.02 (dd, J =9.9, 6.7 Hz, 1H), 3.34 (td, J =6.8, 4.0 Hz, 1H), 1.04-0.91 (m, 1H), 0.50-0.36 (m, 2H), 0.39-0.24 (m, 2H); MS (CIAD ^- ) m/z 395 [MH] ^- .

Example 52 5-{1-fluoro-3-hydroxy-7-[(4 R )-4-hydroxypentyl]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 151)

The title compound was prepared using the procedures described in Example 55 replacing ( R )-pent-4-en-2-ol with 2-methylpent-4-en-2-ol. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.52 (br s, 1H), 7.66 (d, J =8 Hz, 1H), 7.63 (s, 1H) , 7.33 (dd, J =8.2 Hz, 1H), 7.10 (m, 4H), 7.03 (s, J =2 Hz, 1H), 4.35 (d, J =5 Hz , 1H), 4.09 (s, 2H), 3.61 (m, 1H), 2.70 (m, 2H), 1.65 (m, 2H), 1.34 (m, 2H), 1 .04 (d, J = 7 Hz, 3H); MS (ESI ^- ) m/z 381 (MH) ^- .

Example 53 5-{1-Fluoro-3-hydroxy-7-[3- ( dimethylphosphoryl)propoxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 152)

Example 53A: 3-(dimethylphosphoryl)propan-1-ol

A mixture of prop-2-en-1-ol (6.97 ml, 102 mmol) and 2,2'-azobis(2-methylpropionitrile) (AIBN, 0.421 g, 2.56 mmol) was added dropwise to dimethyl-λ ⁵ -phosphanone (4 g, 51.2 mmol) with stirring for 30 minutes at 100° C. under nitrogen. The mixture was stirred for 5 hours at 100°C. Thin layer chromatography (I ₂ , ethyl acetate:methanol=5:1, _Rf =0.25) indicated that the starting material had been consumed. The mixture was then purified by silica gel column chromatography, eluting first with petroleum ether/ethyl acetate (0-100%) and then with methanol/ethyl acetate (0-10%) to give the title compound (4 g, 48.7% yield). %). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.72 (t, J =5.38 Hz, 2H), 1.80-1.98 (m, 4H), 1.53 (d, J = 12.63 Hz, 6H).

Example 53B: 3-(dimethylphosphoryl)propyl methanesulfonate

To a solution of the compound from Example 53A (1.5 g, 11.02 mmol) in dichloromethane (15 mL) was added triethylamine (3.07 mL, 22.04 mmol) followed by dropwise addition of methanesulfonyl chloride (1.030 mL, 13.22 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred for 1 hour at 0°C. Thin layer chromatography (I ₂ , ethyl acetate:methanol=5:1, _Rf =0.3) indicated that the starting material had been consumed. The mixture was quenched with water (50 ml), after which it was extracted with dichloromethane (3×25 ml). The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (500 mg, 16.95% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.31-4.39 (m, 2H), 3.10-3.23 (m, 2H), 2.98-3.08 (m , 3H), 2.05-2.19 (m, 2H), 1.80-1.94 (m, 3H), 1.47-1.61 (m, 6H), 1.39 (t, J =7.34 Hz, 3H).

Example 53C: 5-{3-(benzyloxy)-7-[3-(dimethylphosphoryl)propoxy]-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5 ^- thiadiazolidin-1,1,3-trione

Step 3: To a solution of the compound from example 1H (300 mg, 0.671 mmol) in N,N -dimethylformamide (10 ml) were added in order cesium carbonate (Cs ₂ CO ₃ , 437 mg, 1.342 mmol) and the compound from example 53B (500 mg, 1.867 mmol) at 20°C. Then the reaction mixture was stirred for 4 hours at 80°C. The mixture was quenched with water (50 ml) and acidified to pH=3 with aqueous hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with brine (4 x 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (250 mg, 42.9% yield), which was used in the next step without further purification. MS (IER ^- ) m / z 519 (MH) ^-

Example 53D: 5-{1-Fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione, ammonium salt

To a mixture of the compound from Example 53C (100 mg, 0.115 mmol) in N,N -dimethylformamide (2 mL) and tetrahydrofuran (30 mL) was added 10% Pd/C (30 mg, 0.141 mmol) at 20° C. under argon. The mixture was then stirred for 2 hours at 20° C. under ballooned hydrogen (about 15 psi). Thereafter, the mixture was filtered. The resulting filtrate was concentrated to remove most of the tetrahydrofuran under reduced pressure (< 18° C.) to give a crude product with the remaining N,N -dimethylformamide. One additional 30 mg tube and one additional 50 mg tube were prepared as described above. The three crude reactions were combined and purified by preparative HPLC [Shimadzu LC-8A, Waters Xbridge™ BEH C18 100×25 mm, 5 µm column, flow rate 30 ml/min, 2-23% acetonitrile gradient in buffer (10 mM aqueous ammonium bicarbonate, wavelength: 220 and 254 nm)] and lyophilized to give the title compound as ammonium salt (52 mg, 54.1% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.08-9.77 (m, 1H), 7.67 (d, J =9.01 Hz, 1H), 7.00- 7.20 (m, 6H), 4.13 (t, J =6.13 Hz, 2H), 4.08 (s, 2H), 1.93-2.03 (m, 2H), 1.77 -1.88 (m, 2H), 1.40 (d, J =12.88 Hz, 6H); ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ ppm 7.67 (d, J =9.01 Hz, 1H), 7.11-7.20 (m, 2H), 7.03 (s, 1H), 4.13 (t, J =6.25 Hz, 2H), 4.09 (s, 2H), 1.93-2.04 (m, 2H), 1.77 -1.89 (m, 2H), 1.40 (d, J =12.88 Hz, 6H); MS (ESI ^- ) m / z 429 (MH) ^- .

Example 54 5-{1-Fluoro-3-hydroxy-7-[(4 S )-4-hydroxypentyl]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 153)

The title compound was prepared using the procedures described in Example 55 replacing ( S )-pent-4-en-2-ol with 2-methylpent-4-en-2-ol. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.52 (br s, 1H), 7.66 (d, J =8 Hz, 1H), 7.63 (s, 1H) , 7.33 (dd, J =8.2 Hz, 1H), 7.10 (m, 4H), 7.03 (s, J =2 Hz, 1H), 4.35 (d, J =5 Hz , 1H), 4.09 (s, 2H), 3.61 (m, 1H), 2.70 (m, 2H), 1.65 (m, 2H), 1.34 (m, 2H), 1 .04 (d, J = 7 Hz, 3H); MS (ESI ^- ) m/z 381 (MH) ^- .

Example 55: 5-[1-Fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione ( Compound 154)

Example 55A: 5-{3-(benzyloxy)-1-fluoro-7-[(1E)-4-hydroxy-4-methylpent-1-en-1-yl]naphthalen-2-yl}-1 λ ⁶ , 2,5-thiadiazolidin-1,1,3-trione

A mixture of the compound from Example 1G (0.120 g, 0.258 mmol), 2-(di - tert - butylphosphino ) biphenyl (0.018 g, 0.059 mmol), palladium(II) acetate (0.013 g, 0.059 mmol), 2-methylpent-4- en-2-ol (0.077 g, 0.774 mmol) and triethylamine (0.057 g, 0.567 mmol) in N,N -dimethylformamide (0.8 ml) were placed under a nitrogen atmosphere and then heated to 120°C for 1 hour. The mixture was cooled to ambient temperature, dissolved in methanol (5 ml), filtered through a glass microfiber separator filter and purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 μm column, 50 x 100 mm, flow rate 140 ml/min , 5-70% methanol gradient in buffer (0.025M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide)] to give the title compound (110 mg, 0.227 mmol, 88% yield). MS (ESI ^- ) m/z 483 (MH) ^- .

Example 55B: 5-[1-Fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione

In the compound from example 55A (100 mg, 0.206 mmol) in tetrahydrofuran (4 ml) was added 5 wt. % palladium on carbon (100 mg, 0.438 mmol) in a 20 ml Barnstead Hast C reactor. The mixture was stirred at 50 psi. inch of hydrogen at 25°C for 0.35 hours. Tetrahydrofuran (15 ml) was added and the mixture was filtered. The filtrate was concentrated and the residue was purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 μm column, 50 x 100 mm, flow rate 140 ml/min, 5-70% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound (73 mg, 0.177 mmol, 86% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.67 (s, 1H), 7.64 (d, J =8 Hz, 1H), 7.54 (br s, 4H) , 7.34 (dd, J = 8.2 Hz, 1H), 7.03 (d, J = 2 Hz, 1H), 4.09 (s, 2H), 4.08 (s, 1H) , 2.70 (t, J =7 Hz, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.05 (s, 6H); MS (ESI ^- ) m/z 395 (MH) ^- .

Example 56 5-{1-Fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione (Compound 155)

Example 56A: 2-(1-hydroxycyclopropyl)ethyl 4-methylbenzene-1-sulfonate

Triethylamine (0.355 ml, 2.55 mmol) was added to a solution of 1-(2-hydroxyethyl)cyclopropanol (130 mg, 1.273 mmol) in dichloromethane (5 ml) at 0°C under nitrogen, followed by p -toluenesulfonyl chloride ( 340 mg, 1.782 mmol). The mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with 1 M HCl (10 ml), saturated aqueous NaHCO ₃ (10 ml) and brine (15 ml). The combined organic fractions were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by flash chromatography [12 g SiO ₂ , gradient with ethyl acetate in heptanes from 5% to 50% over 15 minutes] to give the title compound (150 mg, 0.585 mmol, 46.0% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.85-7.77 (m, 2H), 7.39-7.32 (m, 2H), 4.31 (t, J =6 .3 Hz, 2H), 2.46 (s, 3H), 1.91 (t, J =6.3 Hz, 2H), 0.85-0.74 (m, 2H), 0.53-0 .45 (m, 2H).

Example 56B: 5 - {1 - fluoro - 3 - hydroxy - 7 - [(3 - oxopentyl)oxy] naphthalene - 2 - yl} - 1 λ ⁶ ,2,5 - thiadiazolidin - 1,1,3 - trione

A mixture of the compound from example 1H (180 mg, 0.447 mmol), 2-(1-hydroxycyclopropyl)ethyl 4-methylbenzene-1-sulfonate (138 mg, 0.537 mmol) and Cs ₂ CO ₃ (518 mg, 1.590 mmol) in N, N -dimethylformamide (5 ml) was stirred at 50°C for 16 hours. The reaction mixture was treated with 1 ml of 2M Na ₂ CO ₃ and then extracted with ethyl acetate. The organic layer was decanted and the aqueous layer was acidified with 2 N HCl to pH=1-2. The acidic aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 1-10% methanol in dichloromethane to give 5-{3-(benzyloxy)-1-fluoro-7-[2-(1-hydroxycyclopropyl)ethoxy]naphthalen-2-yl}- 1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (290 mg, 0.596 mmol, 75.0% yield). MS (APCI ⁺ ) m/z 487.7 (M+H) ⁺ .

5-{3-(benzyloxy)-1-fluoro-7-[2-(1-hydroxycyclopropyl)ethoxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (200 mg, 0.411 mmol) in tetrahydrofuran (2.0 mL) was added in 5% Pd/C (wet) (60.3 mg, 0.206 mmol) to a 20 mL glass lined RS10 reactor. The mixture was stirred at 50 psi. inch H ₂ at 25°C for 20 hours. The reaction mixture was then filtered and the filtrate was concentrated. The residue was purified by preparative HPLC on a Phenomenex® C8(2) Luna® 5 µm AXIA™ 150×30 mm column, eluted with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 ml/minute (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 give the title compound (26 mg, 0.066 mmol, 15.96% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.66 (dd, J =9.1, 1.6 Hz, 1H), 7.19 (d, J =2.6 Hz, 1H), 7.09 (dd, J =9.0, 2.5 Hz, 1H), 7.03 (d, J =1.4 Hz, 1H), 4.29 (t, J =6.1 Hz, 2H), 4.10 (s, 2H), 2.94 (t, J =6.0 Hz, 2H), 2.58-2.50 (m, 2H), 0.96 (t, J =7.3 Hz, 3H); MS (ESI ⁺ ) m/z 414.2 (M+18) ⁺ .

Example 57 5-[1-Fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 156)

Example 57A : 5-[3-(Benzyloxy)-1-fluoro-7-(3-hydroxybutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione .

The title compound was prepared using the procedures described in Example 104A replacing 4-bromobutan-2-ol with 2-bromoacetonitrile. MS (ESI ^- ) m/z 473 (MH) ^- .

Example 57B: 5-[1-Fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Trichloroborane (1.77 ml , 1.770 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 1.5 hours. The mixture was quenched with ethanol (3 ml) and concentrated. The residue was washed with heptane (4×4 ml) and concentrated to give the crude product. The crude product was purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 µm column, 50 x 100 mm, flow rate 140 ml/min, 5-50% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide )] to give the title compound (45 mg, 0.112 mmol, 50.7% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.66 (dd, J = 8.2 Hz, 1H), 7.24 (br s, 4H), 7.17 (d, J =2Hz, 1H), 7.12(dd, J =8.2Hz, 1H), 7.02(s, 1H), 4.59(d, J =5Hz, 1H), 4.13 (m, 2H), 4.09 (s, 2H), 3.85 (m, 1H), 1.81 (m, 2H), 1.14 (d, J =7 Hz, 3H); MS (ESI ^- ) m/z 383 (MH) ^- .

Example 58: N- [8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide ( Compound 157)

Example 58A: N-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3- methylbutanamide

Mixture of the compound from Example 1G (0.2 g, 0.430 mmol), 3-methylbutanamide (0.078 g, 0.774 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.037 g, 0.064 mmol, Xantphos), cesium carbonate (0.280 g, 0.860 mmol) and palladium (II) acetate (9.65 mg, 0.043 mmol) in dioxane (3 ml) were degassed and filled with nitrogen five times, and then heated to 100°C for 18 hours. The mixture was cooled to ambient temperature and quenched with 0.2 N aqueous HCl (10 ml). The mixture was extracted with ethyl acetate (50×2 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (40 g), eluted with dichloromethane/methanol (0 to 15%) to give the title compound (130 mg, 0.268 mmol, 62.3% yield). MS (ESI ^- ) m/z 484 (MH) ^- .

Example 58B: N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide

Trichloroborane (1.05 ml , 1.050 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 5 minutes and then heated to 0°C for 15 minutes. The mixture was quenched with ethanol (3 ml) and concentrated. The residue was washed with heptane (4×4 ml) and concentrated to give the crude product. The crude product was dissolved in methanol (4 ml) and purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 μm column, 50 x 100 mm, flow rate 140 ml/min, 5-65% gradient of methanol in water (0.1% trifluoroacetic acid)] to give the title compound (40 mg, 0.101 mmol, 57.8% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.40 (br s, 1H), 10.08 (s, 1H), 8.32 (d, J =2 Hz, 1H) , 7.72 (brd, J = 8 Hz, 1H), 7.62 (dd, J = 8.2 Hz, 1H), 7.05 (s, 1H), 4.47 (s, 2H) , 2.23 (d, J =7 Hz, 2H), 2.11 (m, 1H), 0.96 (d, J =7 Hz, 6H); MS (ESI ^- ) m/z 394 (MH) ^- .

Example 59: 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( Compound 158)

Example 59A: 5-[3-(Benzyloxy)-1-fluoro-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3- trion

The title compound was prepared using the procedures described in Example 104A replacing 1,1,1-trifluoro-4-iodobutane with 2-bromoacetonitrile. MS (ESI ^- ) m/z 511 (MH) ^- .

Example 59B: 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione.

The title compound was prepared using the procedures described in Example 137B, replacing the compound from Example 59A with the compound from Example 137A. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.31 (br s, 1H), 7.73 (br d, J =8 Hz, 1H), 7.22 (s, 1H), 7.20(dd, J =8.2Hz, 1H), 7.07(s, 1H), 4.48(s, 2H), 4.15(t, J =8Hz, 2H) , 2.44 (m, 2H), 2.00 (m, 2H); MS (ESI ^- ) m/z 421 (MH) ^- .

Example 60: 1-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy }ethyl)cyclopropane-1-carbonitrile (Compound 159)

The title compound was prepared from the compound of Example 1H and 1-(2-hydroxyethyl)cyclopropanecarbonitrile using the procedures described for Example 56 in 38% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.23 (s, 1H), 7.73 (dd, J =9.1, 1.5 Hz, 1H), 7.26 ( d, J = 2.5 Hz, 1H), 7.19 (dd, J = 9.0, 2.5 Hz, 1H), 7.07 (s, 1H), 4.44 (s, 2H), 4.25 (t, J =6.1 Hz, 2H), 1.99 (t, J =6.1 Hz, 2H), 1.27-1.19 (m, 2H), 1.07-0 .99 (m, 2H); MS (CIAD ^- ) m/z 404.5 (MH) ^-

Example 61: 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ^1,1 , 3-trione (Compound 160)

The title compound was prepared from the compound of Example 1H and 2-(1-(methoxymethyl)cyclopropyl)ethanol using the procedures described for Example 56 in 24% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.33 (s, 1H), 7.71 (dd, J =9.1, 1.5 Hz, 1H), 7.21 ( d, J =2.6 Hz, 1H), 7.16 (dd, J =9.0, 2.5 Hz, 1H), 7.07 (d, J =1.4 Hz, 1H), 4, 50 (s, 2H), 4.17 (t, J =7.1 Hz, 2H), 3.26 (s, 3H), 3.23 (s, 2H), 1.82 (t, J =7 .0 Hz, 2H), 0.49-0.43 (m, 2H), 0.43-0.37 (m, 2H); MS (CIAD ^- ) m/z 423.5 (MH) ^-

Example 62 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin-1,1,3- ^trione (Compound 161)

Example 62A: 5-[3-(benzyloxy)-7-ethenyl-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a mixture of the compound from Example 1G (2 g, 4.17 mmol), vinylboronic acid pinacol ester (3.21 g, 20.85 mmol) and potassium carbonate (1.152 g, 8.34 mmol) in dioxane (200 ml) and water (20 ml) was added 1,1-bis(diphenylphosphino)ferrocene-palladium (II) dichloride complexed with dichloromethane (0.681 g, 0.834 mmol) at 20°C under nitrogen atmosphere. The mixture was then stirred at 80° C. for 18 hours under nitrogen. The reaction mixture was acidified with aqueous 2 M HCl to pH=5 and extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with brine (2×60 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using a flash column (SiO ₂ , ethyl acetate:methanol=10:1) to give the title compound (1.63 g, 3.7 mmol, 89% yield). MS (ESI ^- ) m/z 411 [MH] ^- .

Example 62B: 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carbaldehyde

Sodium periodate (186 mg, 0.869 mmol) was added to a solution of the compound from Example 62A (240 mg, 0.435 mmol) in tetrahydrofuran (5 ml) and water (5.00 ml) at 0°C, and then a solution of osmium tetroxide was added to the mixture (0.275 ml, 0.022 mmol, 0.079 mol/l in t -butyl alcohol). The mixture was then stirred at 0° C. for 3 hours. The reaction was quenched by adding saturated aqueous sodium thiosulfate (20 ml). The mixture was acidified with aqueous 2 M hydrochloric acid to pH=3 and extracted with ethyl acetate (3 x 20 ml). The aqueous layer was washed with ethyl acetate (2×20 ml). The combined organic layers were purified using a reverse phase column [Agela 100 Å SNAP C18 flash column, 330 g, 20 x 35 µm, flow rate 100 ml/min, 0-100% acetonitrile gradient in water] to give the desired aldehyde (380 mg, 0.889 mmol, 28% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.12-10.16 (m, 1 H), 8.60 (s, 1 H), 7.88-8.00 (m , 2 H), 7.58 (br. d, J = 7.28 Hz, 2 H), 7.50 (s, 1 H), 7.29-7.41 (m, 3 H), 5, 33 (s, 2H), 4.10 (s, 2H); MS (ESI ^- ) m/z 413 [MH] ^- .

Example 62C: 5 - (7 - {[(cyclopropylmethyl)amino]methyl} - 1 - fluoro - 3 - hydroxynaphthalene - 2 - yl) - 1 λ ⁶ ,2,5 - thiadiazolidin - 1,1,3 - trione

A 20 ml microwave tube was filled with the compound from Example 62B (100 mg, 0.241 mmol), cyclopropylmethanamine (51.5 mg, 0.724 mmol), N,N -dimethylformamide (3 ml) and acetic acid (0.069 ml, 1.207 mmol). The mixture was stirred for 15 minutes at ambient temperature followed by the addition of sodium cyanoborohydride (91 mg, 1.448 mmol). The reaction mixture was stirred over night at ambient temperature, while there was a precipitate. The mixture was filtered and the collected solid was washed with water to give 5-[3-(benzyloxy)-7-{[(cyclopropylmethyl)amino]methyl}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin- 1,1,3-trione, which was used in the next step without further purification. MS (CIAD ^- ) m / z 468 [MH] ^-

A 250 ml round bottom flask was filled with nitrogen followed by the addition of Pd/C (80 mg, 0.752 mmol) and tetrahydrofuran (10 ml). Then a solution of crude 5-[3-(benzyloxy)-7-{[(cyclopropylmethyl)amino]methyl}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione was added (80 mg, 0.170 mmol) in tetrahydrofuran (2 ml). An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. Volatiles were removed from the filtrate under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0. 1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (20 mg, 0.053 mmol, 31% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.05 (d, J =1.7 Hz, 1H), 7.81 (dd, J =8.6, 1.5 Hz, 1H), 7.53 (dd, J = 8.6, 1.7 Hz, 1H), 7.11 (d, J = 1.3 Hz, 1H), 4.29 (s, 2H), 4, 10 (s, 2H), 2.85 (d, J = 7.4 Hz, 2H), 1.06 (tt, J = 7.8, 4.8 Hz, 1H), 0.63-0.53 (m, 2H), 0.35 (dt, J =6.3, 4.4 Hz, 2H); MS (APCI ⁺ ) m/z 380 [M+H] ⁺ .

Example 63: 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3- ^trione ( Compound 162)

The title compound was prepared using the procedures described in Example 78, replacing 2,2-difluoropropan-1-amine with 2-(azetidin-1-yl)ethanamine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.93 (br s, 1H), 7.52 (br d, J =8 Hz, 1H), 7.11 (dd, J = 8.2 Hz, 1H), 6.93 (s, 1H), 6.85 (d, J = 2 Hz, 1H), 4.44 (s, 2H), 3.59 (m, 2H) .1.67 (t, J =19 Hz, 3H); MS (ESI ^- ) m/z 388 (MH) ^- .

Example 64: 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5 ^- thiadiazolidin-1,1, 3-trione (Compound 163)

Example 64A: tert - butyl (4 - hydroxy - 2,2 - dimethylbutyl) (methyl) carbamate

A mixture of 3,3-dimethyl-4-(methylamino)butan-1-ol hydrochloride (100 mg, 0.596 mmol) and di- tert- butyl dicarbonate (137 mg, 0.626 mmol) in ethyl acetate (1 mL) was stirred at ambient temperature within 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The title compound was used in the next step without purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.27 (s, 1H), 3.51-3.41 (m, 2H), 3.03 (s, 2H), 2, 83 (s, 3H), 1.39 (s, 9H), 1.43-1.33 (m, 2H), 0.85 (s, 6H).

Example 64B: 4 - ((tert - butoxycarbonyl) (methyl) amino) - 3,3 - dimethylbutyl methanesulfonate

To a solution of tert -butyl (4-hydroxy-2,2-dimethylbutyl)(methyl)carbamate (134 mg, 0.579 mmol) in methylene chloride (5 ml) at 0°C were added methanesulfonyl chloride (133 mg, 1.159 mmol) and pyridine (0.094 ml, 1.159 mmol). The mixture was stirred for 15 minutes at 0°C and 2 hours at ambient temperature. Then water (5 ml) was added and the mixture was extracted with methylene chloride (3×5 ml). The organic layers were combined, washed with a saturated solution of copper (II) sulfate (5 ml) and dried with Na ₂ SO ₄ . The volatiles were removed under reduced pressure to give the title compound, which was carried to the next step without purification.

Example 64C: tert-butyl (4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene-2- yl]oxy}-2,2-dimethylbutyl)methylcarbamate

To the product of Example 1H (150 mg, 0.373 mmol) in N,N -dimethylformamide (3 mL) was added cesium carbonate (267 mg, 0.820 mmol) and freshly prepared crude 4-(( tert -butoxycarbonyl)(methyl)amino)-3, 3-dimethylbutyl methanesulfonate (Example 64B, 115 mg, 0.373 mmol). The reaction mixture was stirred overnight at 60°C and 3 hours at 80°C. After cooling to ambient temperature, methanol (1 ml) was added and the volatiles were removed under reduced pressure. The residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm x 25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (55 mg, 0.089 mmol, 24% yield over 3 stages). MS (CIAD ^- ) m / z 614 [MH] ^- .

Example 64D: 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 , ^2,5 -thiadiazolidin-1,1, 3-trione

A 250 ml round bottom flask was filled with nitrogen followed by the addition of Pd/C (35 mg, 0.329 mmol) and tetrahydrofuran (10 ml). Then a solution of the compound from example 64C (35 mg, 0.057 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. The volatiles were removed under reduced pressure and the crude material was carried to the next step without purification. MS (CIAD ^- ) m/z 524 [MH] ^- .

Crude tert -butyl (4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene- 2-yl]oxy}-2,2-dimethylbutyl)methylcarbamate (30 mg, 0.057 mmol), methylene chloride (2 ml) and trifluoroacetic acid (2 ml) at ambient temperature. The reaction mixture was stirred for 30 minutes. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (15 mg, 0.035 mmol, 62% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.43 (s, 1H), 8.06 (s, 2H), 7.61 (dd, J =9.0, 1.5 Hz, 1H), 7.17 (d, J =2.5 Hz, 1H), 7.06 (dd, J =9.0, 2.5 Hz, 1H), 6.97 (d, J =1 .3 Hz, 1H), 4.09 (t, J = 6.8 Hz, 2H), 4.05 (s, 2H), 2.88-2.80 (m, 2H), 2.55 (t , J =5.1 Hz, 3H), 1.76 (t, J =6.8 Hz, 2H), 0.99 (s, 6H); MS (APCI ⁺ ) m/z 426 [M+H] ⁺ .

Example 65 5-{1-Fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione (Compound 164)

The title compound was prepared using the procedures described in Example 80 replacing 2-phenylethanamine with 2-methoxyethanamine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.74 (br s, 1H), 7.53 (br d, J =8 Hz, 1H), 7.31 (m, 4H), 7.21(m, 1H), 7.05(dd, J =8.2Hz, 1H), 6.92(s, 1H), 6.72(d, J =2Hz, 1H) , 4.37 (s, 2H), 3.34 (t, J =8 Hz, 2H), 2.92 (t, J =8 Hz, 2H); MS (ESI ^- ) m/z 414 (MH) ^- .

Example 66 5-[7-(3-Amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3-trione (Compound 165)

Example 66A: 3 - ((tert - butoxycarbonyl)amino) -3 - methylbutyl methanesulfonate

To a solution of tert -butyl (4-hydroxy-2-methylbutan-2-yl)carbamate (200 mg, 0.984 mmol) in methylene chloride (5 ml) at 0°C was added methanesulfonyl chloride (135 mg, 1.181 mmol) and pyridine (0.159 ml , 1.968 mmol). The reaction was stirred for 15 minutes at 0°C and 2 hours at ambient temperature. Then water (5 ml) was added and the mixture was extracted with dichloromethane (3×5 ml). The organic layers were combined, washed with a saturated solution of CuSO ₄ (2 ml) and dried over Na ₂ SO ₄ . The volatiles were removed under reduced pressure to give crude 3-(( tert -butoxycarbonyl)amino)-3-methylbutyl methanesulfonate, which was carried to the next step without purification.

Example 66B: tert-butyl (4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene-2- yl]oxy}-2-methylbutan-2-yl)carbamate

To the product from example 1H (150 mg, 0.373 mmol) in N,N -dimethylformamide (3 ml) was added cesium carbonate (267 mg, 0.820 mmol) and freshly prepared 3-(( tert -butoxycarbonyl)amino)-3-methylbutyl methanesulfonate ( 210 mg, 0.746 mmol, example 66A). The reaction mixture was stirred overnight at 60°C and 3 hours at 80°C. After cooling to ambient temperature, methanol (1 mL) was added, the volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm) . 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (14 mg, 0.024 mmol, 7% yield over two stages). MS (CIAD ^- ) m/z 586 [MH] ^- .

Example 66C: 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 , ^2,5 -thiadiazolidin-1,1,3-trione

A 250 ml round bottom flask was filled with nitrogen followed by the addition of Pd/C (14 mg, 0.132 mmol) and tetrahydrofuran (10 ml). A solution of the product of example 66B (35 mg, 0.057 mmol) in tetrahydrofuran (2 ml) was then added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. Volatiles were removed from the filtrate under reduced pressure, and the residue was carried to the next stage without purification. MS (CIAD ^- ) m/z 496 [MH] ^- .

Crude tert -butyl (4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene- 2-yl]oxy}-2-methylbutan-2-yl)carbamate (11.8 mg, 0.024 mmol) in methylene chloride (2 ml). The mixture was treated with trifluoroacetic acid (2 ml) at ambient temperature and stirred for 30 minutes at room temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (6 mg, 0.015 mmol, 64% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.48 (s, 1H), 7.83 (s, 2H), 7.69 (dd, J =9.2, 1.5 Hz, 1H), 7.25 (d, J =2.6 Hz, 1H), 7.15 (dd, J =9.0, 2.5 Hz, 1H), 7.04 (d, J =1 .4 Hz, 1H), 4.23 (t, J = 6.5 Hz, 2H), 4.10 (s, 2H), 2.12-2.04 (m, 2H), 1.34 (s , 6H); MS (CIAD ⁺ ) m/z 398 [M+H] ⁺ .

Example 67 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione (Compound 166)

The title compound was prepared using the procedures described in Example 78, replacing 4,4,4-trifluorobutan-1-amine with 2-(azetidin-1-yl)ethanamine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.72 (br s, 1H), 7.51 (br d, J =8 Hz, 1H), 7.01 (dd, J = 8.2 Hz, 1H), 6.93 (s, 1H), 6.67 (d, J = 2 Hz, 1H), 4.37 (s, 2H), 3.18 (t, J = 8 Hz, 2H), 2.40 (m, 2H), 1.82 (m, 2H); MS (ESI ^- ) m/z 420 (MH) ^- .

Example 68 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 167)

Example 68A: 5-[3-(Benzyloxy)-7-(difluoromethyl)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carbaldehyde (70 mg, 0.167 mmol, Example 62B ) in dichloromethane (12 ml) was added diethylaminosulfur trifluoride (0.662 ml, 5.01 mmol) at -70°C, then the mixture was stirred for 1 hour at 0°C and 19 hours at 20°C. The reaction was quenched by adding saturated ammonium bicarbonate solution (20 ml). The mixture was then acidified with aqueous hydrochloric acid (1 N) to pH=2. An additional reaction per 0.01 g and one reaction per 0.07 g was prepared and carried out as described above. The combined reactions were extracted with ethyl acetate (3 x 30 ml). The organic layers were combined and washed with water (2×30 ml) and brine (2×30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (140 mg, 0.128 mmol, 26.6% yield), which was used in the next step without further purification. MS (ESI ^- ) m/z 435 (MH) ^- .

Example 68B: 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from example 68A (130 mg, 0.119 mmol) in dichloromethane (3 ml) was added boron trichloride (1.192 ml, 1.192 mmol) at -70°C and the mixture was stirred for 15 minutes at -70°C. The reaction was quenched by adding methanol (5 ml). An additional reaction per 0.01 g was prepared and carried out as described above. The mixtures were combined and concentrated under reduced pressure. The residue was then purified by preparative HPLC [Nano-Micro UniSil 5-100 C18 ULTRA 5 µm, 100×250 µm, flow rate 25 ml/min, 10-100% acetonitrile gradient in water (10 mM aqueous ammonium bicarbonate)] to give the title compound (3.2 mg, 8.62 µmol, 5.53% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.10 (s, 1 H), 7.87 (d, J =8.80 Hz, 1 H), 7.62 (d, J = 8.80 Hz, 1 H), 7.27 (s, 1 H), 7.15 (s, 1 H), 7.13 (s, 1 H), 6.99 (s, 1 H) , 4.21 (s, 2H); ¹⁹ F NMR (377 MHz, DMSO- d ₆ ) δ ppm -125.51 -125.37 (m, 1 F) -108.36, -108.12 (m, 2 F); MS (ESI ^- ) m/z 345 (MH) ^- .

Example 69: 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H- pyrrol -3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione (Compound 168)

Example 69A: 5-[7-(2,5-dihydro-1H-pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trion

Boron trichloride (3.43 ml, 3.43 mmol) was added dropwise to a solution of the compound from Example 14A (200 mg, 0.343 mmol) in dichloromethane (5 ml) at -70°C. The mixture was stirred for 2 hours at -70° C. under nitrogen. The reaction was quenched with methanol (4 ml) at -70° C. and the resulting mixture was concentrated under reduced pressure to give the title compound (130 mg, 0.304 mmol, 89% yield), which was used in the next step without further purification. MS (ESI ^- ) m/z 362 (MH) ^- .

Example 69B: 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3 - hydroxynaphthalen-2-yl}-1 λ ^6.2.5 -thiadiazolidin-1,1,3-trione

To a solution of the compound from Example 69A (100 mg, 0.234 mmol) in N,N -dimethylformamide (3 mL) were added in order N,N -diisopropyethylamine (0.409 mL, 2.339 mmol) and dimethylphosphine chloride (105 mg, 0.936 mmol) at 0 °C The reaction was stirred for 12 hours at 25°C. The reaction solution was purified by reverse phase chromatography [Agela Claricep™ Flash AQ C18 column, 20-35 µm, 100 Å, 40 g, flow rate 50 ml/min, 5-100% acetonitrile gradient in water] and lyophilized to give crude specified in the connection header. The crude title compound was purified by preparative silica gel thin layer chromatography (ethyl acetate:methyl alcohol=2:1) to give the title compound (12 mg, 0.027 mmol, 8.98% yield). ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 7.63-7.66 (m, 1 H), 7.47-7.57 (m, 2 H), 6.86-6 .89 (m, 1 H), 6.24-6.28 (m, 1 H), 4.39-4.46 (m, 2 H), 4.31-4.36 (m, 2 H) , 4.14-4.20 (m, 2 H), 1.50-1.59 (m, 1 H); MS (ESI ^- ) m / z 438 (MH) ^- .

Example 70: 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione (Compound 169)

The title compound was prepared using the procedures described in Example 78, replacing 3,3,3-trifluoropropan-1-amine with 2-(azetidin-1-yl)ethanamine. 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 (ESI ^- ) m/z 406 (MH) ^- .

Example 71: 5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione ( Connection 170)

Example 71A: 3-methoxy-3-methylbutyl methanesulfonate

To a solution of 3-methoxy-3-methylbutan-1-ol (200 mg, 1.692 mmol) in methylene chloride (5 ml) at 0°C was added methanesulfonyl chloride (388 mg, 3.38 mmol) and triethylamine (0.354 ml, 2. 54 mmol). The reaction mixture was stirred at 0°C for 30 minutes and 2 hours at ambient temperature. Then water (5 ml) was added and the mixture was extracted with methylene chloride (3×5 ml). The organic layers were combined, washed with brine (2 ml) and dried over Na ₂ SO ₄ . The volatiles were removed under reduced pressure to give the title compound, which was carried to the next step without purification.

Example 71B: 5-[3-(Benzyloxy)-1-fluoro-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trion

To a solution of the compound from example 1H (150 mg, 0.373 mmol) in N,N -dimethylformamide (3 ml) was slowly added a freshly prepared solution of 3-methoxy-3-methylbutyl methanesulfonate (161 mg, 0.820 mmol, example 71A) in N,N - dimethylformamide (1 ml). The reaction was stirred overnight at 50°C and 3 hours at 80°C. After cooling to ambient temperature, methanol (1 ml) was added and the volatiles were removed under reduced pressure. The residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm x 25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (49 mg, 0.098 mmol, yield 26.2 %). MS (CIAD ^- ) m / z 501 [MH] ^- .

Example 71C: 5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3-trione

A 250 ml round bottom flask was filled with nitrogen followed by the addition of Pd/C (40 mg, 0.376 mmol) and tetrahydrofuran (10 ml). Then a solution of the compound from example 71B (40 mg, 0.080 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. Volatiles were removed from the filtrate under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0. 1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (14 mg, 0.034 mmol, 9.03% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.34 (s, 1H), 7.71 (dd, J =9.1, 1.4 Hz, 1H), 7.22 ( d, J = 2.6 Hz, 1H), 7.17 (dd, J = 9.0, 2.5 Hz, 1H), 7.07 (d, J = 1.3 Hz, 1H), 4, 51 (s, 2H), 4.14 (t, J =7.2 Hz, 2H), 3.13 (s, 3H), 1.97 (t, J =7.2 Hz, 2H), 1, 19 (s, 6H); MS (CIAD ^- ) m/z 411 [MH] ^- .

Example 72 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 171)

Example 72A: 5-[3-(benzyloxy)-7-(2-cyclopropylpropoxy)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a suspension of the compound from Example 1H (120 mg, 0.298 mmol) in N,N -dimethylformamide (3 mL) was added cesium carbonate (214 mg, 0.656 mmol) and (1-bromopropan-2-yl)cyclopropane (107 mg, 0.656 mmol). The mixture was heated to 90°C for 2 hours. After cooling, the mixture was filtered and the filtrate was concentrated. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) in for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (59 mg, 0.122 mmol, 41% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.80 (dd, J =9.8, 1.5 Hz, 1H), 7.56-7.48 (m, 2H), 7.43-7.34 (m, 3H), 7.37-7.29 (m, 1H), 7.33-7.23 (m, 2H), 5.24 (s, 2H), 4, 46 (s, 2H), 4.10 (dd, J =9.4, 5.0 Hz, 1H), 3.98 (dd, J =9.4, 7.0 Hz, 1H), 1.31 -1.20 (m, 1H), 1.09 (d, J =6.7 Hz, 3H), 0.73 (dtd, J =13.3, 8.6, 4.9 Hz, 1H), 0.50-0.37 (m, 2H), 0.26 (ddd, J =10.4, 4.7, 1.8 Hz, 1H), 0.14 (ddd, J =9.3, 4 .8, 1.6 Hz, 1H); MS (CIAD ^- ) m/z 483 [MH] ^- .

Example 72B: 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A 250 ml round bottom flask was filled with nitrogen followed by the addition of Pd/C (45 mg, 0.423 mmol) and tetrahydrofuran (10 ml). Then a solution of the compound from example 72A (45 mg, 0.093 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) in for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (13 mg, 0.033 mmol, 7.79% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.33 (s, 1H), 7.71 (dt, J =8.1, 1.4 Hz, 1H), 7.19 ( d, J = 8.1 Hz, 2H), 7.07 (s, 1H), 4.50 (s, 2H), 4.08 (dd, J = 9.3, 5.1 Hz, 1H), 3.95 (dd, J =9.3, 7.1 Hz, 1H), 1.26 (tt, J =9.3, 6.1 Hz, 1H), 1.08 (d, J =6, 7 Hz, 3H), 0.78-0.67 (m, 1H), 0.49-0.38 (m, 2H), 0.25 (ddd, J =10.9, 4.8, 2, 2 Hz, 1H), 0.13 (ddd, J =9.3, 4.8, 1.7 Hz, 1H); MS (CIAD ^- ) m/z 393 [MH] ^- .

Example 73: 5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-1 λ 6 ,2,5 ^- thiadiazolidine -1,1,3-trione (Compound 172)

The title compound was prepared using the procedures described in Example 80 replacing 2-isopropoxyethanamine with 2-methoxyethanamine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.46 (brd, J =8 Hz, 1H), 7.01 (dd, J =8.2 Hz, 1H), 6 .89 (s, 1H), 6.66 (d, J =2 Hz, 1H), 5.78 (d, t=6 Hz, 1H), 4.07 (s, 2H), 3.60 (m, 1H), 3.57 (t, J =8 Hz, 2H), 3.23 (m, 2H), 1.11 (d, J =8 Hz, 6H); MS (ESI ^- ) m/z 396 (MH) ^- .

Example 74: 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione (Compound 173)

The title compound was prepared as described for Example 56B from the compound from Example 1H and 3-(bromomethyl)-1-methylsulfonylpyrrolidine in 39.7% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.14 (s, 1H), 7.68 (dd, J =9.0, 1.5 Hz, 1H), 7.21 ( d, J = 2.6 Hz, 1H), 7.16 (dd, J = 9.0, 2.5 Hz, 1H), 7.03 (s, 1H), 4.38 (s, 2H), 4.06 (cd, J =9.6, 6.8 Hz, 2H), 3.50-3.41 (m, 2H), 3.28-3.20 (m, 1H), 3.10 ( dd, J =10.1, 6.9 Hz, 1H), 2.88 (s, 3H), 2.72 (n, J =7.2 Hz, 1H), 2.07 (m, 1H), 1.77 (m, 1H); MS (CIAD ^- ) m/z 472.3 (MH) ^- .

Example 75: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}butanonitrile ( Compound 174)

The title compound was prepared using the procedures described in Example 78, replacing 4-aminobutanonitrile with 2-(azetidin-1-yl)ethanamine. ¹ H NMR (500 MHz, -d ₆ ) δ ppm 10.15 (br s, 1H), 7.96 (br s, 1H), 7.53 (d, J =8 Hz, 1H ), 7.07 (dd, J = 8.2 Hz, 1H), 6.95 (br s, 1H), 6.80 (br s, 1H), 4.47 (s, 2H), 3 .17(t, J =8Hz, 2H), 2.60(m, 2H), 1.87(m, 2H); MS (ESI ^- ) m/z 377 (MH) ^- .

Example 76 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 175)

Example 76A: 5-[3-(Benzyloxy)-1-fluoro-7-(prop-2-en-1-yl)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin- ^1,1 , 3-trione

To a solution of the compound from Example 1G in 1,4-dioxane (5 mL) was added allylboronic acid pinacol ester (280 mg, 1.668 mmol), potassium carbonate (173 mg, 1.251 mmol) and [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium (II), complex with dichloromethane (Pd(dppf)Cl ₂ ,CH ₂ Cl ₂ , 34.0 mg, 0.042 mmol) at 25°C under nitrogen, and the reaction mixture was stirred at 80°C for 16 hours in a nitrogen atmosphere. An additional 30 mg reaction was prepared and carried out as described above. The resulting mixtures were combined and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 0 to 20% methanol/dichloromethane) to give the title compound (120 mg, 0.27 mmol, 64.8% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.77 (d, J= 8.33 Hz, 1 H), 7.72 (s, 1 H), 7.56 (d, J= 7.45 Hz, 2 H), 7.34-7.41 (m, 3 H), 7.28-7.33 (m, 2 H), 5.95-6.13 (m, 1 H), 5.22-5.26 (m, 2 H), 5.06-5.16 (m, 2 H), 4.07-4.09 (m, 2 H), 3.51-3 .56 (m, 2 H), 3.12-3.21 (m, 4 H); MS (ESI ^- ) m / z 425 (MH) ^- .

Example 76B: [6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetaldehyde

To a solution of the compound from Example 76A (1 g, 2.345 mmol) in tetrahydrofuran (15 ml) and water (5 ml) was added sodium periodate (1.003 g, 4.69 mmol) at 20°C, followed by addition of osmium tetroxide (1 M in tert -butanol, 0.117 ml, 0.117 mmol) at 0°C. The mixture was stirred at 0°C for 3 hours. The reaction was then quenched with saturated aqueous sodium sulfite (150 ml). The mixture was acidified with aqueous hydrochloric acid (1 M) to pH=5 and then extracted with ethyl acetate (3×100 ml). The aqueous layer was filtered and purified using reverse phase chromatography [Agela Claricep™ Flash AQ C18 column, 20-35 µm, 100 Å, 120 g flash column, flow rate 50 ml/min, 0-100% acetonitrile gradient in water] to give the title compound (500 mg, 1.167 mmol, 24.8% yield). MS (ESI ^- ) m / z 427 (MH) ^- .

Example 76C: 5-[3-(Benzyloxy)-1-fluoro-7-(2-hydroxyethyl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from example 76B (200 mg, 0.327 mmol) in tetrahydrofuran (2 ml) was added sodium borohydride (37.1 mg, 0.980 mmol) at 0°C and the mixture was stirred for 2 hours at 0°C. The reaction was quenched by adding water (15 ml) at 25°C, followed by stirring for 5 minutes. The resulting mixture was extracted with ethyl acetate (3 x 20 ml). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [Kromasil column 150×25 mm, 10 μm, C18, flow rate 25 ml/min, 10-100% gradient of acetonitrile in water (0.04% ammonium hydroxide and ammonium bicarbonate, 10 mM)] with yielding the title compound (30 mg, 0.063 mmol, 19.41% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.70-7.75 (m, 1 H), 7.51-7.57 (m, 2 H), 7.39-7 .44 (m, 1 H), 7.32-7.38 (m, 2 H), 7.25-7.32 (m, 2 H), 7.17-7.21 (m, 1 H) , 7.06 (s, 1 H), 6.91-6.96 (m, 1 H), 5.15-5.28 (m, 2 H), 4.08 (s, 2 H), 3 .65 (t, J= 6.84 Hz, 1 H), 2.79-2.92 (m, 2 H); MS (ESI ⁺ ) m / z 431 (M+H) ⁺ .

Example 76D: 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, ammonium salt

To a solution of the compound from example 76C (28 mg, 0.059 mmol) in methanol (15 ml) was added 10% Pd/C (6.30 mg) at 20°C under nitrogen atmosphere. The suspension was degassed in vacuo and purged several times with hydrogen, after which the reaction was stirred for 2 hours at 20°C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [5 µm Waters Xbridge™ column 150×25 µm, flow rate 50 ml/min, 25-100% acetonitrile gradient in aqueous ammonium bicarbonate (10 mM)] to give the title compound as the ammonium salt (2.3 mg, 6.29 µmol, 9.39% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.57-9.67 (m, 1 H), 7.61-7.70 (m, 2 H), 7.35 (dd , J= 8.44, 1.47 Hz, 1 H), 7.17-7.26 (m, 1 H), 7.08-7.16 (m, 1 H), 7.02 (s, 1 H), 6.91-7.00 (m, 1 H), 4.59-4.70 (m, 1 H), 4.06-4.10 (m, 2 H), 3.64- 3.68(m, 2H), 3.64-3.64(m, 1H), 3.16-3.18(m, 1H), 2.84-2.87(m, 2H ); ¹ H NMR (400 MHz, DMSO- d ₆ /D ₂ O) δ ppm 7.66-7.68 (m, 1 H), 7.61-7.65 (m, 1 H), 7 .33-7.38 (m, 1 H), 7.00-7.04 (m, 1 H), 4.05-4.13 (m, 2 H), 3.65-3.66 (m , 2 H), 3.13-3.16 (m, 1 H), 2.80-2.88 (m, 2 H); MS (ESI ⁺ ) m / z 341 (M+H) ⁺ .

Example 77: 5-[7-(4-Amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 176)

Example 77A: 4-{[6-(Benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} -2,2-dimethylbutanonitrile

To a solution of the compound from Example 1H (100 mg, 0.249 mmol) in N,N -dimethylformamide (3 mL) was added sodium hydride (21.87 mg, 0.547 mmol) in three portions at ambient temperature. The reaction was stirred for 30 minutes until the end of the release of bubbles. A solution of 4-bromo-2,2-dimethylbutanonitrile (96 mg, 0.547 mmol) in N,N -dimethylformamide (2 ml) was slowly added to the reaction mixture. The reaction was stirred overnight at ambient temperature. Methanol (2 ml) was added, the solvents were removed under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , 10% methanol in dichloromethane) to give the title compound (65 mg, 0.131 mmol, 53% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.77 (dd, J =9.1, 1.4 Hz, 1H), 7.59-7.50 (m, 2H), 7.44-7.26 (m, 5H), 7.20 (dd, J =9.0, 2.5 Hz, 1H), 5.22 (s, 2H), 4.28 (t, J = 6.5 Hz, 2H), 4.09 (s, 2H), 3.17 (d, J = 5.2 Hz, 1H), 2.12-2.05 (m, 2H), 1.41 ( s, 6H); MS (CIAD-) m / z 496 (MH) ^- .

Example 77B: 5-[7-(4-Amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3-trione

Example 77A (26 mg, 0.052 mmol) and acetic acid (1 mL) were added in 10% Pd/C, dry (48 mg, 0.451 mmol) in a 20 mL Barnstead Hast C reactor. The reaction was stirred for 45 hours at ambient temperature at 117 psi inch of hydrogen gas. The reaction mixture was filtered, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (9 mg, 0.022 mmol, 4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.50 (s, 1H), 7.75 (d, J =1.4 Hz, 1H), 7.73 (broad, 2H) , 7.31 (d, J =2.6 Hz, 1H), 7.19 (dd, J =9.0, 2.5 Hz, 1H), 7.12-7.07 (m, 1H), 4.22 (t, J =6.8 Hz, 2H), 4.15 (s, 2H), 2.85 (s, 2H), 1.88 (t, J =6.8 Hz, 2H), 1.10 (s, 6H); MS (CIAD ⁺ ) m/z 412 [M+H] ⁺ .

Example 78: 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione (Compound 177)

Example 78A: 5-[7-{[2-(azetidin-1-yl)ethyl]amino}-3-(benzyloxy)-1-fluoronaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione

Mixture of the compound from Example 1G (93 mg, 0.2 mmol), BrettPhos Pd G3 (10.88 mg, 0.012 mmol), 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) was degassed and filled with nitrogen five times and then heated to 105°C for 3 hours. Dichloromethane/methanol (10:1, 50 ml) was added to the mixture, followed by 4 M HCl in dioxane (0.2 ml). The mixture was stirred for 10 minutes and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (12 g), eluted with dichloromethane/methanol (0 to 65%) to give the title compound (85 mg, 0.175 mmol, 88% yield). MS (ESI ^- ) m/z 483 (MH) ^- .

Example 78B: 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trion

Trichloroborane ( 1.672 ml, 1.672 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 20 minutes, heated to 0°C for 30 minutes, then quenched with ethanol (4 ml). The mixture was stirred at ambient temperature for 5 minutes and concentrated. The residue was washed with dichloromethane (4×4 ml) and dried to give the title compound (40 mg, 0.093 mmol, 100% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.38 (br s, 1H), 10.12 (br s, 1H), 7.55 (br d, 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 (ESI ^- ) m/z 393 (MH) ^- .

Example 79: 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione (Compound 178)

Example 79A tert -butyl 3-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] oxy}azetidine-1-carboxylate

A mixture of the compound from Example 1H (150 mg, 0.373 mmol), Cs ₂ CO ₃ (243 mg, 0.746 mmol) and tert -butyl 3-iodoazetidine-1-carboxylate (106 mg, 0.373 mmol) in N,N- dimethylformamide (1 ml) was stirred at ambient temperature for 4 hours. The mixture was heated to 60°C for 14 hours. After cooling, a 2N Na ₂ CO ₃ solution (0.5 ml) was added and the mixture was extracted with 20 ml of ethyl acetate. The organic layer was decanted and the aqueous layer was acidified with acetic acid (0.25 ml) and extracted with ethyl acetate (2×25 ml). The combined ethyl acetate fractions were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound, which was used in the next step without further purification. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.85 (dd, J =9.1, 1.3 Hz, 1H), 7.55-7.48 (m, 2H), 7.42 (s, 1H), 7.38 (t, J = 7.3 Hz, 2H), 7.36-7.30 (m, 1H), 7.26 (dd, J = 8.9, 2.5 Hz, 1H), 7.06 (d, J = 2.6 Hz, 1H), 5.24 (s, 2H), 5.17 (tt, J = 6.4, 3.9 Hz, 1H), 4.43 (d, J =2.7 Hz, 2H), 4.37 (s, 2H), 3.85 (dd, J =10.0, 3.7 Hz, 2H), 1, 40 (s, 9H).

Example 79B: 5-{7-[(azetidin-3-yl)oxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trion

A mixture of the compound from example 79A (190 mg, 0.341 mmol) and trifluoroacetic acid (0.5 ml) in CH ₂ Cl ₂ (3 ml) was stirred at ambient temperature for 4 hours and then at 60°C for 14 hours . The mixture was concentrated to give the title compound, which was used in the next step without further purification. MS (APCI ⁺ ) m/z 469.8 (M+H) ⁺ .

Example 79C: 5-[3-(Benzyloxy)-7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoronaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione

Cyclopropanesulfonyl _chloride (23.97 _mg , 0.171 mmol), The mixture was stirred at ambient temperature for 14 hours. The mixture was diluted with ethyl acetate, washed with 0.1 N HCl and brine, dried over Na ₂ SO ₄ and concentrated to give the title compound, which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.82 (dd, J =9.1, 1.5 Hz, 1H), 7.52-7.46 (m, 2H), 7.39 (s, 1H), 7.38-7.29 (m, 3H), 7.25 (dd, J =9.0, 2.6 Hz, 1H), 7.10 (d, J = 2.6 Hz, 1H), 5.21 (m, 3H), 4.44-4.32 (m, 4H), 3.95 (dd, J =9.3, 4.5 Hz, 2H), 2.81-2.74 (m, 1H), 1.06-0.99 (m, 2H), 0.93 (dd, J =4.6, 2.4 Hz, 2H).

Example 79D: 5 - (7 - {[1 - (cyclopropanesulfonyl) azetidin - 3 - yl] oxy} - 1 - fluoro - 3 - hydroxynaphthalene - 2 - yl) - 1 λ ⁶ .2.5 - thiadiazolidin - 1.1 ,3 - trion

The above compound from Example 79C (35 mg, 0.062 mmol) and 20% wet Pd(OH) ₂ (70 mg, 0.254 mmol) in tetrahydrofuran (2 mL) were stirred at 50 psi. inch H ₂ for 50 hours. The mixture was filtered, concentrated and purified by preparative HPLC on a Phenomenex C8(2) Luna 5 μm AXIA™ 150 x 30 mm column, gradient of 5-100% acetonitrile (A) in 0.1% trifluoroacetic acid in water (B) at speed flow 50 ml/minute to give the title compound (8 mg, 0.017 mmol, 27.2% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.22 (s, 1H), 7.76 (dd, J =9.1, 1.4 Hz, 1H), 7.20 ( dd, J =9.0, 2.6 Hz, 1H), 7.08 (s, 1H), 7.06 (d, J =2.6 Hz, 1H), 5.22 (tt, J =6 .5, 4.7 Hz, 1H), 4.44-4.32 (m, 4H), 3.98 (dd, J = 9.3, 4.6 Hz, 2H), 2.82 (tt, J = 7.9, 4.8 Hz, 1H), 1.09-0.99 (m, 2H), 1.02-0.93 (m, 2H); MS (CIAD ^- ) m/z 469.8 (MH) ^- .

Example 80 5-{1-Fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3-trione ⁽ Compound 179)

Mixture of the compound from Example 1G (93 mg, 0.2 mmol), BrettPhos Pd G3 (10.88 mg, 0.012 mmol), BrettPhos (6.44 mg, 0.012 mmol), cesium carbonate (195 mg, 0.600 mmol) and 2 -methoxyethanamine (30.0 mg, 0.400 mmol) in 2-methylbutan-2-ol (2 ml) was degassed and filled with nitrogen five times, and then heated to 105°C for 3 hours. Dichloromethane/methanol (10:1, 50 ml) was added to the mixture, followed by 4 M HCl in dioxane (0.2 ml). The mixture was stirred for 10 minutes and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (40 g), eluted with dichloromethane/methanol (0 to 35%) to give the title compound (20 mg, 0.054 mmol, 27.1% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.87 (br s, 1H), 7.46 (br d, J =8 Hz, 1H), 7.01 (dd, J = 8.2 Hz, 1H), 6.89 (s, 1H), 6.65 (d, J = 2 Hz, 1H), 5.85 (t, J = 5 Hz, 1H), 4.07 (s, 2H), 3.53 (m, 2H), 3.28 (s, 3H), 3.26 (m, 1H), 2.97 (m, 1H); MS (ESI ^- ) m/z 368 (MH) ^- .

Example 81: 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( Connection 180)

Example 81A 5-(3-(benzyloxy)-1-fluoro-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

The title compound was prepared using the procedures described in Example 104A, replacing 3,3,3-trifluoropropylmethanesulfonate with 2-bromoacetonitrile. MS (ESI ^- ) m/z 497 (MH) ^- .

Example 81B: 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

The title compound was prepared using the procedures described in Example 137B, replacing the compound from Example 81A with the compound from Example 137A. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.20 (br s, 1H), 7.72 (br d, J =8 Hz, 1H), 7.27 (d, J = 2 Hz, 1H), 7.18 (dd, J = 8.2 Hz, 1H), 7.09 (s, 1H), 4.40 (s, 2H), 4.33 (t, J = 8 Hz, 2H), 2.84 (m, 2H); MS (ESI ^- ) m/z 407 (MH) ^- .

Example 82: 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}methyl )cyclopropane-1-carbonitrile (Compound 181)

In a 20 mL vented tube, the product of Example 1G (0.605 g, 1.3 mmol), cesium carbonate (1.271 g, 3.90 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (BrettPhos Pd G3 precatalyst, 0.035 g, 0.039 mmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 0.021 g, 0.039 mmol). The solids were placed under vacuum for 5 minutes at ambient temperature, then the tube was filled with nitrogen followed by tert -amyl alcohol (12 mL) and 1-(aminomethyl)cyclopropanecarbonitrile (0.25 g, 2.60 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 90°C. After 73 hours the reaction mixture was cooled to ambient temperature, then extinguished with 1 M hydrochloric acid (6 ml) and diluted with ethyl acetate (6 ml). The aqueous layer was extracted with ethyl acetate (2×6 ml). The combined organic layers were washed 4:1 with brine and 1M hydrochloric acid (3 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 2-[3-(benzyloxy)-7-{[(1 -cyanocyclopropyl)methyl]amino}-1-fluoronaphthalen-2-yl]-4-oxo-1λ ⁴ ,2,5-thiadiazolidin-1,1-bis(olate), which was used for the next reaction without purification. MS (CIAD ^- ) m/z 479 [MH] ^- .

To a suspension of crude 2-[3-(benzyloxy)-7-{[(1-cyanocyclopropyl)methyl]amino}-1-fluoronaphthalen-2-yl]-4-oxo-1λ ⁴ ,2,5-thiadiazolidin-1, 1-bis(olate) (0.625 g, 1.301 mmol) and pentamethylbenzene (0.386 g, 2.60 mmol) in dichloromethane (12 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (7.8 ml, 1 M , 7.8 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (5 ml) followed by anhydrous ethanol (5 ml). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The solid was triturated with heptanes (3 x 5 ml) followed by dichloromethane (2 x 3 ml). The triturated product was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber filter separator. The resulting solution was directly purified by preparative HPLC [Waters XBridge™ C18 5 µm OBD column, 50 x 100 mm, flow rate 100 ml/min, gradient 5-40% methanol in buffer (0.1% trifluoroacetic acid in water by v/v)] to give the title compound (0.2446 g, 0.627 mmol, 48.2% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.05 (s, 1H), 7.54 (dd, J =9.0, 1.5 Hz, 1H), 7.10 ( dd, J = 8.9, 2.3 Hz, 1H), 6.94 (s, 1H), 6.79 (d, J = 2.3 Hz, 1H), 4.49 (s, 2H), 3.33 (s, 2H), 1.25 (k, J =4.6 Hz, 2H), 1.13-1.04 (m, 2H); MS (ESI ^- ) m/z 389 [MH] ^- .

Example 83: 5-[1-Fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione ( Compound 182)

Example 83A: 5-[3-(Benzyloxy)-1-fluoro-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trion

Mixture of the compound from example 1H (100 mg, 0.249 mmol), 4-bromo-2-methylbutan-2-ol (49.8 mg, 0.298 mmol) and Cs ₂ CO ₃ (162 mg, 0.497 mmol) in N, N - dimethylformamide (1 ml) was stirred at ambient temperature for 14 hours. The mixture was diluted with ethyl acetate and 0.2 N HCl (15 ml). The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound, which was used in the next step without further purification. MS (CIAD ^- ) m/z 487.5 (MH) ^- .

Example 83B: 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione

The compound from Example 83A (120 mg, 0.246 mmol) in tetrahydrofuran (6 mL) was added to a 20 mL Barnstead Hast C reactor filled with 5% Pd/C, wet (145 mg, 0.681 mmol). The mixture was stirred under a hydrogen pressure of 150 psig. inch for 25 hours 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, 66.4% 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 84 5-{1-fluoro-3-hydroxy-7-[3-(1 H -pyrazol-1-yl)propoxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (Compound 183)

Example 84A: 5-{3-(Benzyloxy)-1-fluoro-7-[3-(1H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione

Mixture of the product of example 1H (125 mg, 0.31 mmol), 1-(3-chloropropyl) -1H- pyrazole (89.8 mg, 0.62 mmol) and cesium carbonate (304 mg, 0.93 mmol) in N,N -dimethylformamide (2 ml) was stirred at 50°C for 14 hours. The reaction mixture was filtered and purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 µm 100 Å AXIA™ column (50 mm × 30 mm), eluted with a gradient of 5-100% acetonitrile (A) and 0.1 % trifluoroacetic acid in water (B) at a flow rate of 40 ml/minute to give the title compound. MS (APCI ⁺ ) m/z 511.1 (M+H) ⁺ .

Example 84B: 5-{1-Fluoro-3-hydroxy-7-[3-(1H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trion

To a solution of the compound from Example 84A (101.4 mg, 0.199 mmol) in tetrahydrofuran (2 mL) was added 5% Pd/C (wet JM#9) (200 mg, 0.876 mmol). The mixture was stirred in a 4 ml high-pressure 150 psi hydrogen bottle. inch within 28 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by reverse-phase preparative HPLC on a 5 μm Waters XBridge™ C8 column (75 mm × 30 mm), eluted with a gradient of 5-100% methanol (A) and 25 mM ammonium bicarbonate buffer ( pH 10) in water (B) at a flow rate of 40 ml/minute to give the title compound. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (d, J =2.1 Hz, 1H), 7.71 (dd, J =9.1, 1.4 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.28-7.14 (m, 2H), 7.08 (s, 1H), 6.28 (t, J = 2 .0 Hz, 1H), 4.35 (t, J =6.8 Hz, 2H), 4.17 (s, 2H), 4.05 (t, J =6.2 Hz, 2H), 2, 30 (n, J =6.6 Hz, 2H); MS (ESI ⁺ ) m / z 421.3 (M+H) ⁺ .

Example 85 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H- pyrrol -3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 184)

Example 85A: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole hydrochloride

Into a solution of tert -butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1 H -pyrrole-1-carboxylate (5 g, 16 09 mmol) in ethyl acetate (5 ml) was added dropwise a solution of hydrochloric acid in ethyl acetate (20 ml, 80 mmol, 4 M) at 0°C and the mixture was stirred for 2 hours at 25°C. The mixture was concentrated under reduced pressure to give the title compound (4 g, 16.09 mmol, 97% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.76 (br s, 2H), 6.42 (d, J= 1.98 Hz, 1H), 3.96 (br s, 1H), e, J= 10.80 Hz, 4H), 1.23 (s, 12H).

Example 85B: 1-[(4-nitrophenyl)methanesulfonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole

To a solution of the compound from example 85A (0.983 g, 4.24 mmol) in tetrahydrofuran (20 ml) was added dropwise potassium tert -butoxide (9.34 ml, 9.34 mmol, 1 M in tetrahydrofuran) at 0°C. After stirring for 5 minutes at 0°C, (4-nitrophenyl)methanesulfonyl chloride (1 g, 4.24 mmol) was added portionwise to the mixture at 0°C, and then the resulting mixture was stirred for 12 hours at 25°C. The mixture was then concentrated under reduced pressure, and the crude title compound (2 g, about 40% pure) was used in the next step without further purification. MS (IER ^- ) m / z 311 (M-83) ^- .

Example 85C: 5-[3-(Benzyloxy)-1-fluoro-7-{1-[(4-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalene-2-yl] -1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Tetrakis[triphenylphosphine]palladium (0.234 g, 0.203 mmol) and sodium carbonate ( Na ₂ CO ₃ , 0.538 g, 5.07 mmol) under nitrogen, and the resulting mixture was stirred at 80° C. for 12 hours under nitrogen. The mixture was diluted with water (75 ml) and brought to pH=3 with HCl (1 M). The mixture was then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (150 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by reverse phase chromatography [Agela Claricep™ Flash AQ C18 column, 20-35 µm, 100 Å, 330 g flash column, flow rate 100 ml/min, 0-100% acetonitrile gradient in water] to give the indicated in the title compound (420 mg, 0.525 mmol, 25.9% yield). MS (IER ^- ) m / z 651 (MH) ^- .

Example 85D: 5-(1-Fluoro-3-hydroxy-7-{1-[(4-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalene-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from Example 85C (420 mg, 0.579 mmol) in dichloromethane (30 mL) was added boron trichloride (5.79 mL, 5.79 mmol, 1 M in dichloromethane) dropwise at -70°C and the mixture was stirred for 2 hours at 25°C. The mixture was then quenched with methanol (10 mL) and the mixture was concentrated under reduced pressure to give the title compound (350 mg, 0.498 mmol, 86% yield), which was used in the next step without further purification. MS (ESI ^- ) m / z 561 (MH) ^- .

Example 85E: 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione

Iron powder (278 mg, 4.98 mmol) and ammonium chloride (266 mg, 4.98 mmol) at 20°C. Then the reaction mixture was stirred for 2 hours at 90°C. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [10 µm column Waters Xbridge™ Prep OBD C18 150 x 40 mm, flow rate 50 ml/min, 10-35% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] and lyophilized to give the title compound (42 mg, 0.071 mmol, 14.34% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.00 (br s, 1H), 7.68-7.80 (m, 2H), 7.64 (s, 1H), 7.21 (s, 1H), 7.01-7.14 (m, 4H), 6.95 (s, 1H), 6.49-6.59 (m, 2H), 6.43 (br. s, 1H), 4.52 (br s, 2H), 4.38 (s, 2H), 4.13 (s, 4H); ¹⁹ F NMR (377 MHz, DMSO- d ₆ ) δ ppm -125.43 (br s, 1F); MS (IER ^- ) m / z 531 (MH) ^- .

Example 86 5-[1-Fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 185)

Example 86A: 5-[3-(Benzyloxy)-1-fluoro-7-(hydroxymethyl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from example 62B (250 mg, 0.595 mmol) in methanol (10 ml) was added sodium borohydride (NaBH ₄ , 25 mg, 0.654 mmol) at 20° C. and the mixture was stirred for 30 minutes. The reaction was quenched by adding aqueous hydrochloric acid (1 N) to pH=5, the mixture was added to 20 ml of brine, and the resulting mixture was extracted with ethyl acetate (2×40 ml). The organic layers were combined, washed with brine (2×40 ml), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (210 mg, 0.438 mmol, 73.7% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.89-7.93 (m, 1 H), 7.82-7.88 (m, 1 H), 7.49-7 .58 (m, 3 H), 7.43-7.47 (m, 1 H), 7.30-7.42 (m, 3 H), 5.24-5.31 (m, 2 H) , 4.63-4.71(m, 2H), 4.51-4.56(m, 2H); MS (ESI ^- ) m/z 415 (MH) ^- .

Example 86B: 5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from example 86A (0.05 g, 0.104 mmol) in dichloromethane (1 ml) was added boron trichloride (1.044 ml, 1.044 mmol) at -70°C and the mixture was stirred for 15 minutes at -70°C. The reaction was then quenched by adding 20 ml of methanol. An additional reaction per 0.01 g was prepared and carried out as described above. The mixture was concentrated under reduced pressure. The residue was then purified by preparative HPLC [5 µm Xtimate™ C18 column, 25 x 150 mm, flow rate 25 ml/min, 10-100% acetonitrile in water gradient (10 mM ammonium bicarbonate)] to give the title compound (0.011 g, 0.033 mmol, 26.6% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.75-7.81 (m, 1 H), 7.62-7.70 (m, 1 H), 7.37-7 .44 (m, 1 H), 7.01-7.06 (m, 1 H), 4.58-4.60 (m, 2 H), 4.12 (s, 2 H); MS (ESI ^- ) m/z 325 (MH) ^-

Example 87: 5-{7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 , ^2,5 -thiadiazolidin-1,1,3- trione (Compound 186)

In a 4 ml tube, the NiCl ₂ adduct of dimethoxyethane (3.97 mg, 0.018 mmol, 0.12 equiv.) and 4,4'-di -tert -butyl-2,2'-dipyridyl (4.85 mg, 0.018 mmol , 0.12 eq.) in N,N -dimethylacetamide (1.0 ml). Example 1G (70 mg, 0.15 mmol, 1.0 eq), (1-( tert -butoxycarbonyl)piperidin-3-yl)potassium trifluoroborate (88 mg, 0.301 mmol, 2.0 eq) was added , cesium carbonate (98 mg, 0.30 mmol, 2.0 eq.) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium (1+), 2- (2-pyridyl)pyridine, hexafluorophosphate (5.0 mg, 0.005 mmol, 0.03 eq) followed by dioxane (1.0 ml). The reaction was irradiated overnight using a 450 nm diode photoreactor.

The reaction was filtered and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give t -butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]piperidine-1-carboxylate (23 .9 mg, 28% yield. The residue was treated with 4 M HCl in dioxane (1 ml). Volatiles were removed in a stream of nitrogen.

In a 4 ml tube, 5-[3-(benzyloxy)-1-fluoro-7-(piperidin-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( 0.020 g, 0.042 mmol) was treated with N,N -dimethylformamide (0.5 ml). N -ethyl- N -isopropylpropan-2-amine (0.022 ml, 0.126 mmol) was added followed by cyclopropanesulfonyl chloride (6.42 μl, 0.063 mmol). The reaction was stirred overnight at ambient temperature. The reaction was filtered and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to obtain a mixture of sulfonated material 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione and free amine.

5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( 13.1 mg, 0.023 mmol) and tetrahydrofuran (1 ml) were added in 5% Pd/C (wet JM#9) (45 mg, 0.197 mmol) in a 4 ml high pressure balloon and stirred for 38 hours at 75 lb/ sq. inch of hydrogen without external heating. The reaction was filtered and the filtrate was concentrated under a stream of nitrogen. The reaction was reduced in dimethyl sulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compound eluted at 4.27-4.66 minutes (10 mg, 91% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.78 (s, 1H), 7.71 (d, J =8.4 Hz, 1H), 7.46 (d, J = 9.4 Hz, 1H), 7.07 (s, 1H), 4.19 (d, J =40.7 Hz, 3H), 3.00 (dd, J =24.5, 13.4 Hz, 4H), 2.68-2.58(m, 1H), 2.07-1.53(m, 4H), 1.33-1.12(m, 1H), 1.09-0.76( m, 3H); MS (ESI ^- ) m/z 481.8 (MH) ⁺ .

Example 88: 5-{7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trione (Compound 187)

In a 4 ml tube, the NiCl ₂ adduct of dimethoxyethane (3.97 mg, 0.018 mmol, 0.12 equiv.) and 4,4'-di -tert -butyl-2,2'-dipyridyl (4.85 mg, 0.018 mmol , 0.12 eq.) in N,N -dimethylacetamide (1.0 ml). Example 1G (70 mg, 0.15 mmol, 1.0 eq), (1-( tert -butoxycarbonyl)pyrrolidin-2-yl)potassium trifluoroborate (83 mg, 0.301 mmol, 2.0 eq) was added , cesium carbonate (98 mg, 0.30 mmol, 2.0 eq.) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium (1+), 2- (2-pyridyl)pyridine, hexafluorophosphate (5.0 mg, 0.005 mmol, 0.03 eq) followed by dioxane (1.0 ml). The reaction was irradiated overnight using a 450 nm diode photoreactor.

The reaction was filtered and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give t -butyl 2-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidine-1-carboxylate (69 .2 mg, 83% yield. The residue was treated with 1 ml of 4 M HCl in dioxane. Volatiles were removed in a stream of nitrogen.

The residue (28.5 mg, 0.06 mmol) was dissolved in N,N -dimethylformamide (1.0 ml). N -ethyl- N -isopropylpropan-2-amine (33 µl, 0.19 mmol, 3.0 eq.) was added, followed by cyclopropanecarbonyl chloride (7.4 µl, 0.08 mmol, 1.3 eq. ). The reaction was stirred overnight at ambient temperature. The reaction was filtered and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give 5-{ 3-(benzyloxy)-7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (22.5 mg, 69% yield.

B 5-{3-(benzyloxy)-7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (22.5 mg, 0.043 mmol) and tetrahydrofuran (1 ml) were added 5% Pd/C (wet JM#9) (38 mg, 0.166 mmol) in a 4 ml high pressure balloon. The reaction was stirred for 18 hours at 75 psi. inch of hydrogen without external heating. Methanol (2 ml) was added and the reaction mixture was hydrogenated for ~32 hours. The reaction mixture was filtered and concentrated under a stream of nitrogen. The residue was reconstituted in dimethylsulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (11.3 mg, 39% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.82-7.51 (m, 2H), 7.34 (d, J =8.7 Hz, 1H), 7.09 ( s, 1H), 5.55-4.93 (m, 1H), 4.13 (d, J =1.0 Hz, 2H), 3.93-3.50 (m, 2H), 2.47 -2.21 (m, 1H), 2.11-1.30 (m, 4H), 0.81-0.18 (m, 4H); MS (APCI ⁺ ) m/z 434.3 (M+H) ⁺ .

Example 89 5-{1-fluoro-3-hydroxy-7-[2-(1 H -pyrazol-1-yl)ethoxy]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (Compound 188)

The title compound was prepared from the compound of Example 1H and 1-(2-bromoethyl) -1H -pyrazole as described for Example 84. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7 .83 (d, J =2.2 Hz, 1H), 7.69 (dd, J =9.2, 1.4 Hz, 1H), 7.52 (d, J =2.0 Hz, 1H) , 7.22 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 9.0, 2.6 Hz, 1H), 7.07 (s, 1H), 6.31 ( t, J =2.1 Hz, 1H), 4.58 (t, J =5.0 Hz, 2H), 4.47 (t, J =5.1 Hz, 2H), 4.17 (s, 2H); MS (ESI ⁺ ) m / z 407.6 (M+H) ⁺ .

Example 90: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trione (Compound 189)

5-[3-(Benzyloxy)-1-fluoro-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione was obtained using the oxidative -reduction reactions under the action of light, described in example 88. The residue (28.5 mg, 0.06 mmol) was dissolved in N,N -dimethylformamide (1.0 ml). N -ethyl- N -isopropylpropan-2-amine (33 µl, 0.19 mmol, 3.0 eq.) was added, followed by cyclopropanesulfonyl chloride (8.3 µl, 0.08 mmol, 1.3 eq. ). The reaction was stirred overnight at ambient temperature. The reaction was filtered and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give 5-{ 3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (16.0 mg, 46% yield.

5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( 16 mg, 0.029 mmol) and tetrahydrofuran (1 mL) were added in 5% Pd/C (wet JM#9) (18 mg, 0.079 mmol) in a 4 mL high pressure balloon and stirred for 20 hours at 75 psi. inch of hydrogen without external heating. The reaction mixture was filtered and concentrated under a stream of nitrogen. The reaction was reduced in dimethyl sulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (3.9 mg, 13% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.83 (s, 1H), 7.75 (d, J =8.6 Hz, 1H), 7.51 (dd, J = 8.7, 1.8 Hz, 1H), 7.11 (s, 1H), 5.15-5.04 (m, 1H), 4.18 (d, J =1.7 Hz, 2H), 3.70-3.53 (m, 2H), 2.76-2.69 (m, 1H), 2.51-2.44 (m, 1H), 2.09-1.73 (m, 3H ), 1.09-0.87 (m, 4H); MS (APCI ⁺ ) m/z 470.2 (M+H) ⁺ .

Example 91 5-[7-(oxolan-2-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 190)

5-[3-(Benzyloxy)-1-fluoro-7-(oxolan-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione was obtained using the oxidative -reduction reactions under the influence of light, described in example 88, using the compound from example 1G (1 eq.), tetrahydrofuran-2-carboxylic acid (1.5 eq.), bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridyl]phenyl]iridium (1+), 2-(2-pyridyl)pyridine, hexafluorophosphate (0.02 eq.), NiCl ₂ adduct of dimethoxyethane (0.05 eq.), 4.4′ -di- tert -butyl-2,2'-dipyridyl (0.05 equiv.), Cs ₂ CO ₃ (1.5 equiv.) in N,N -dimethylacetamide (0.025 M). The reaction was irradiated for 72 hours, using 450 nm blue diodes. The reaction was purified by reverse phase preparative HPLC on a 5 µm Waters XBridge™ C8 column (75 mm x 30 mm). A gradient of methanol (A) and ammonium acetate in water (B) was used at a flow rate of 40 ml /minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give 5-[3-(benzyloxy)-1-fluoro-7-(oxolan-2-yl)naphthalene-2-yl]- 1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (4.0 mg).

5-[3-(benzyloxy)-1-fluoro-7-(oxolan-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (4 mg, 8 .76 µmol) and tetrahydrofuran (1 ml) were added in 5% Pd/C (wet JM#9) (10 mg, 0.044 mmol) in a 4 ml high pressure balloon and stirred for 20 hours at 75 psi. inch of hydrogen and 25°C. The reaction mixture was filtered and the solvent was removed under a stream of nitrogen. The residue was dissolved in methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (1.1 mg, 34% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.79 (s, 1H), 7.71 (d, J =8.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.08 (s, 1H), 4.95 (t, J = 7.2 Hz, 1H), 4.14 (s, 2H), 4.04 (k, J = 7.1 Hz, 1H), 3.86 (d, J = 7.4 Hz, 1H), 2.04-1.92 (m, 3H), 1.72 (dd, J = 12.3, 7 .9 Hz, 1H); MS (ESI ^- ) m/z 365.1 (MH) ⁺ .

Example 92 5-[1-Fluoro-3-hydroxy-7-(piperidin-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 191 )

The title compound was isolated during preparation of the compound of Example 87 resulting in partial sulfonylation (1.5 mg) and eluted from 3.80-4.15 minutes. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.87-7.63 (m, 2H), 7.44 (d, J =9.5 Hz, 1H), 7.08 ( s, 1H), 4.14 (s, 2H), 3.35-3.18 (m, 2H), 3.04-2.99 (m, 2H), 2.90-2.82 (m, 1H), 2.01-1.87 (m, 2H), 1.84-1.68 (m, 2H); MS (ESI ^- ) m/z 378.1 (MH) ⁺ .

Example 93: 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3- trione (Compound 192)

Example 93A: 5-{3-(benzyloxy)-7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoronaphthalen-2-yl}-1 λ 6 ,2,5 ^- thiadiazolidin-1,1, 3-trione

To a solution of 5-[3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, ammonium salt, product of Example 1H (200 mg , 0.497 mmol), in N,N -dimethylformamide were added cesium carbonate (356 mg, 1.093 mmol) and 2-(2-bromoethyl)-1,1-difluorocyclopropane (202 mg, 1.093 mmol). The mixture was heated to 80°C for 2 hours. After cooling, the reaction mixture was filtered, the volatiles were removed, and the residue was subjected to column chromatography (SiO ₂ , dry load with diatomaceous earth, 5% methanol in dichloromethane) to give the title compound (115 mg, 0.227 mmol, 46% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.76 (dd, J =9.1, 1.5 Hz, 1H), 7.60-7.48 (m, 2H), 7.45-7.32 (m, 2H), 7.36-7.26 (m, 2H), 7.26 (d, J =2.5 Hz, 1H), 7.21 (dd, J = 8.9, 2.5 Hz, 1H), 5.22 (s, 2H), 4.25-4.15 (m, 1H), 4.20-4.01 (m, 1H), 4.08 (s, 2H), 2.01 (k, J = 9.9, 8.5 Hz, 1H), 1.93-1.72 (m, 2H), 1.65-1.51 (m, 1H ), 1.25 (dtd, J =14.9, 7.3, 3.5 Hz, 1H); MS (CIAD ^- ) m/z 505 [MH] ^- .

Example 93B: 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3- trion

A 250 ml round bottom flask was filled with nitrogen followed by the addition of Pd/C (8.40 mg, 0.079 mmol) and tetrahydrofuran (10 ml). Then a solution of the compound from example 93A (40 mg, 0.079 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (12 mg, 0.029 mmol, 37% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.72 (dd, J =9.1, 1.4 Hz, 1H), 7.22 (d, J =2.6 Hz, 1H), 7.19 (dd, J = 8.9, 2.5 Hz, 1H), 7.07 (s, 1H), 4.45 (s, 2H), 4.22-4.11 (m , 2H), 2.03-1.95 (m, 1H), 1.88-1.79 (m, 2H), 1.63-1.52 (m, 1H), 1.29-1.22 (m, 1H); MS (CIAD ^- ) m/z 415 [MH] ^- .

Example 94 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3-trione (Compound 193)

Example 94A: 5-{3-(benzyloxy)-1-fluoro-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3 -trione

To a solution of the compound from Example 1H (130 mg, 0.323 mmol) in N,N -dimethylformamide (3 mL) was added cesium carbonate (232 mg, 0.711 mmol) and 1-(2-bromoethyl)-1-methylcyclopropane (105 mg, 0.646 mmol). The mixture was heated to 80°C for 2 hours. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (SiO ₂ , dry load with diatomaceous earth, 10% methanol in dichloromethane) to give the title compound (107 mg, 0.221 mmol, 68% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (dd, J =9.0, 1.4 Hz, 1H), 7.59-7.53 (m, 2H), 7.45-7.27 (m, 4H), 7.26 (d, J =2.5 Hz, 1H), 7.18 (dd, J =9.0, 2.5 Hz, 1H), 5 .22 (s, 2H), 4.19 (t, J = 6.9 Hz, 2H), 4.11 (s, 2H), 1.74 (t, J = 6.9 Hz, 2H), 1 .12 (s, 3H), 0.43-0.37 (m, 2H), 0.30-0.23 (m, 2H); MS (CIAD ^- ) m/z 483 [MH] ^- .

Example 94B: 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione

A 250 ml round bottom flask was filled with nitrogen followed by the addition of 5% Pd/C (8.79 mg, 0.083 mmol) and tetrahydrofuran (10 ml). Then a solution of the compound from example 94A (40 mg, 0.083 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (11 mg, 0.028 mmol, 34% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.70 (dd, J =9.0, 1.5 Hz, 1H), 7.22 (d, J =2.6 Hz, 1H), 7.17 (dd, J =9.0, 2.5 Hz, 1H), 7.06 (s, 1H), 4.46 (s, 2H), 4.17 (t, J =6 .9 Hz, 2H), 1.73 (t, J =6.9 Hz, 2H), 1.11 (s, 3H), 0.43-0.33 (m, 2H), 0.33-0 .24 (m, 2H); MS (CIAD ^- ) m/z 393 [MH] ^- .

Example 95 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H- pyrrol -3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 194)

Example 95A: 1-[(3-nitrophenyl)methanesulfonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole

To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H- pyrrole hydrochloride (1 g, 4.10 mmol) in tetrahydrofuran (10 ml) was added potassium tert -butoxide (9.03 ml, 1 M in tetrahydrofuran) at 0°C, after stirring for 5 minutes, (3-nitrophenyl)methanesulfonyl chloride (0.967 g, 4.10 mmol) was added dropwise to the mixture ) was added at 0°C. The resulting mixture was stirred for 12 hours at 25°C. The mixture was then concentrated under reduced pressure to give the title compound (2 g, 2.029 mmol, 49.5% yield), which was used for the next step without further purification. MS (IER ^- ) m / z 311 (M-83) ^- .

Example 95B: 5-[3-(Benzyloxy)-1-fluoro-7-{1-[(3-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalene-2-yl] -1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Sodium carbonate (Na ₂ CO ₃ , 0.538 g, 5.07 mmol) and tetrakis [triphenylphosphine]palladium (0.234 g, 0.203 mmol) under nitrogen, and the resulting mixture was heated to 80° C. for 12 hours under nitrogen. One additional reaction per 400 mg was prepared and carried out as described above. The mixtures were combined and diluted with water (100 ml). The mixture was adjusted to pH=3 with aqueous hydrochloric acid (1 M) and then the mixture was extracted with ethyl acetate (3×80 ml). The combined organic phase was washed with brine (3×50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography [Agela Claricep™ Flash AQ C18 column, 20-35 µm, 100 Å, 330 g flash column, flow rate 100 ml/min, 10-100% acetonitrile gradient in water] to give the indicated in the title compound (280 mg, 0.331 mmol, 80% purity) and the title compound (120 mg, 0.16 mmol, 90% purity). MS (IER ^- ) m / z 651 (MH) ^- .

Example 95C: 5-(1-Fluoro-3-hydroxy-7-{1-[(3-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalene-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from Example 95B (50 mg, 0.054 mmol) in dichloromethane (30 ml) was added boron trichloride (0.536 ml, 0.536 mmol, 1 M in dichloromethane) dropwise at -70°C and the mixture was stirred for 2 hours at 25 °C. One additional 280 mg tube was prepared and reacted as described above. Each mixture was then concentrated under reduced pressure. Residues were pooled and purified by preparative HPLC [10 µm Waters Xbridge™ Prep OBD C18 150 x 40 mm column, flow rate 50 ml/min, 20-40% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] to give the title compound (180 mg, 0.176 mmol, 72.5% yield). MS (ESI ^- ) m / z 561 (MH) ^- .

Example 95D: 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione

Iron powder (170 mg, 3.04 mmol) and ammonium chloride (163 mg, 3.04 mmol) at 20°C. Then the reaction mixture was stirred for 2 hours at 90°C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [5 µm column Waters Xbridge™ Prep OBD C18 150 x 25 mm, flow rate 25 ml/min, 10-40% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] and lyophilized to give the title compounds (55 mg, 0.095 mmol, 31.4% yield, ammonium salt). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.71 (br s, 2H), 7.60 (s, 1H), 7.07 (s, 1H), 6.95 ( br t, J = 7.76 Hz, 1H), 6.67 (br s, 1H), 6.50-6.62 (m, 2H), 6.41 (br s, 1H), 4 .49 (br s, 2H), 4.38 (s, 2H), 4.21 (br s, 2H), 4.12 (s, 2H); ¹⁹ F NMR (377 MHz, DMSO- d ₆ ) δ ppm -125.50 (br s, 1F); MS (IER ^- ) m / z 531 (MH) ^- .

Example 96 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H- pyrrol -3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 195)

Example 96A: 1-[(2-nitrophenyl)methanesulfonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole

To a solution of the compound from Example 85A (1 g, 4.10 mmol) in tetrahydrofuran (10 ml) was added potassium tert -butoxide (9.03 ml, 9.03 mmol, 1 M in tetrahydrofuran) at 0°C, and after stirring (2-nitrophenyl)methanesulfonyl chloride (0.967 g, 4.10 mmol) was added dropwise to the mixture over 5 minutes at 0°C. The resulting mixture was stirred for 12 hours at 25°C, after which the mixture was concentrated under reduced pressure to give the title compound (2 g, 2.029 mmol, 49.5% yield), which was used in the next step without further purification. MS (IER ^- ) m / z 311 (M-83) ^- .

Example 96B: 5-[3-(Benzyloxy)-1-fluoro-7-{1-[(2-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalene-2-yl] -1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Sodium carbonate (Na ₂ CO ₃ , 0.538 g, 5.07 mmol) and tetrakis [triphenylphosphine]palladium (0.234 g, 0.203 mmol) under nitrogen and the mixture was stirred at 80° C. for 12 hours under nitrogen. One additional 400 mg tube was prepared as described above. The mixtures were combined and diluted with water (100 ml). The mixture was adjusted to pH=3 with aqueous hydrochloric acid (1 M) and then the mixture was extracted with ethyl acetate (3×80 ml). The combined organic phase was washed with brine (3×50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase chromatography [Agela Claricep™ Flash AQ C18 column, 20-35 µm, 100 Å, 330 g flash column, flow rate 100 ml/min, 0-100% acetonitrile gradient in water] to give the indicated in the title compound (320 mg, 85% purity) and the title compound (90 mg, 95% purity). MS (IER ^- ) m/z 651 (MH) ^-

Example 96C: 5-(1-Fluoro-3-hydroxy-7-{1-[(2-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalene-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from Example 96B (50 mg, 0.054 mmol) in dichloromethane (30 ml) was added boron trichloride (0.536 ml, 0.536 mmol, 1 M in dichloromethane) dropwise at -70°C and the mixture was stirred for 2 hours at 25 °C. One additional 320 mg tube was prepared and reacted as described above. The mixtures were then concentrated under reduced pressure to give residues which were combined and purified by preparative HPLC [10 µm column Waters Xbridge™ Prep OBD C18, 150 x 40 mm, flow rate 50 ml/min, 10-40% gradient of acetonitrile in aqueous bicarbonate ammonium (10 mM)] to give the title compound (180 mg, 0.176 mmol, 37.4% yield). MS (ESI ^- ) m / z 561(MH) ^- .

Example 96D: 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione, ammonium salt

To a solution of the compound from Example 96C (180 mg, 0.304 mmol) in ethanol (20 mL), methanol (20 mL) and water (4.00 mL) were added iron powder (170 mg, 3.04 mmol) and ammonium chloride in order. (163 mg, 3.04 mmol) at 20°C. Then the reaction mixture was stirred for 2 hours at 90°C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [5 µm column Waters Xbridge™ Prep OBD C18, 150 x 25 mm, flow rate 25 ml/min, 10-40% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] and lyophilized to give the indicated title compound (42 mg, 0.074 mmol, 24.41% yield, ammonium salt). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.04 (s, 1H), 7.69-7.78 (m, 2H), 7.62 (s, 1H), 7, 21 (s, 1H), 7.12 (d, J = 7.45 Hz, 1H), 7.05-7.09 (m, 2H), 6.97-7.03 (m, 1H), 6 .96 (s, 1H), 6.66 (d, J = 7.45 Hz, 1H), 6.50 (t, J = 7.45 Hz, 1H), 6.45 (br s, 1H) , 5.19 (br s, 1H), 4.61 (br s, 2H), 4.49 (s, 2H), 4.25 (br s, 2H), 4.12 (s, 2H ); ¹⁹ F NMR (377 MHz, DMSO- d ₆ ) δ ppm -125.55 (br s, 1F); MS (IER ^- ) m / z 531 (MH) ^- .

Example 97 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 196)

Example 97A: 5-[3-(benzyloxy)-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl]-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione

To a solution of the compound from Example 1G (500 mg, 1.042 mmol) in dioxane (20 mL) were added in order bis(pinacolato)diboron (662 mg, 2.61 mmol), potassium acetate (307 mg, 3.13 mmol) and [ 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed with dichloromethane (76 mg, 0.104 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 3 hours under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of methanol in dichloromethane (0 to 20%) to give the title compound (460 mg, 0.718 mmol, 68.9% yield). MS (IER ^- ) m / z 511 (MH) ^- .

Example 97B: 5-[3-(Benzyloxy)-7-(2,2-difluoroethyl)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from Example 97A (20 mg, 0.031 mmol) in N -methyl-2-pyrrolidinone (0.5 mL) was added 1,1-difluoro-2-iodoethane (25 mg, 0.120 mmol), potassium phosphate solution (21 .8 mg, 0.100 mmol) in water (0.12 ml) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl) ]palladium (II) (XPhos Pd G2, 3 mg, 3.5 μmol) at 25°C under nitrogen, the reaction mixture was heated to 80°C and stirred for 18 hours at 80°C under nitrogen. An additional fourteen reactions per 0.5 g were prepared and carried out as described above. The combined reactions were diluted with water (150 ml). The resulting mixture was extracted with ethyl acetate (3 x 150 ml). The combined organic phases were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [5 µm Waters Xbridge™ Prep OBD C18 column, 150 x 25 mm, flow rate 25 ml/min, 25-100% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] to give the title compound (7 mg, 0.015 mmol, 3.25% yield). ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 7.91 (s, 1 H), 7.75-7.80 (m, 1 H), 7.54-7.59 (m , 2 H), 7.44-7.48 (m, 1 H), 7.34-7.41 (m, 2 H), 7.21-7.32 (m, 2 H), 5.91 -6.26 (m, 1 H), 5.21-5.28 (m, 2 H), 4.36-4.42 (m, 2 H), 3.31 (s, 3 H); MS (ESI ^- ) m / z 449 (MH) ^- .

Example 97C: 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3-trione

To a solution of the compound from Example 97B (5 mg, 10.88 µmol) in dichloromethane (1.5 ml) was added boron trichloride (1 M in dichloromethane, 0.033 ml, 0.03 mmol) at -70°C. The reaction mixture was stirred at -70°C for 2 hours. The reaction was quenched by adding methanol (1.5 ml) at -78°C. An additional 2 mg reaction was prepared and carried out as described above. The resulting mixtures of the above two reactions were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC [Kromasil 150×25mm column, 10 µm, C18, flow rate 25 ml/min, 25-100% acetonitrile gradient in aqueous ammonium bicarbonate (10 mM)] to give the title compound (1.8 mg, 4.68 µmol, 30.1% yield. ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 7.81-7.89 (m, 1 H), 7.61-7.70 (m, 1 H), 7.35-7 .45 (m, 1 H), 7.02-7.09 (m, 1 H), 5.89-6.23 (m, 1 H), 4.36-4.42 (m, 2 H) , 3.22-3.30 (m, 2H); MS (ESI ^- ) m / z 359 (MH) ^- .

Example 98: 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( Compound 197)

Example 98A: 5-[3-(Benzyloxy)-1-fluoro-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3- trion

The title compound was prepared using the procedures described in Example 104A, replacing 2,2,2-trifluoroethyl methanesulfonate with 2-bromoacetonitrile. MS (ESI ^- ) m/z 483 (MH) ^- .

Example 98B: 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

The title compound was prepared using the procedures described in Example 137B, replacing the compound from Example 98A with the compound from Example 137A. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.68 (br s, 1H), 7.78 (br d, J =8 Hz, 1H), 7.41 (d, J =2Hz, 1H), 7.29(dd, J =8.2Hz, 1H), 7.16(s, 1H), 4.91(m, 2H), 4.55(s, 2H) ; MS (ESI ^- ) m/z 483 (MH) ^- .

Example 99 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 198)

Example 99A: 5-[3-(Benzyloxy)-1-fluoro-7-(2-fluoroethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

The title compound was prepared using the procedures described in Example 104A, replacing 2-fluoroethyl 4-methylbenzenesulfonate with 2-bromoacetonitrile. MS (ESI ^- ) m/z 447 (MH) ^- .

Example 99B: 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

The title compound was prepared using the procedures described in Example 137B, replacing the compound from Example 99A with the compound from Example 137A. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.38 (br s, 1H), 7.73 (br d, J =8 Hz, 1H), 7.25 (d, J =2Hz, 1H), 7.23(dd, J =8.2Hz, 1H), 7.10(s, 1H), 4.86(m, 1H), 4.74(m, 1H) , 4.47 (s, 2H), 4.39 (m, 1H), 4.32 (m, 1H); MS (ESI ^- ) m/z 357 (MH) ^- .

Example 100: 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl )cyclopropane-1-carbonitrile (Compound 199)

Example 100A: 1-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy }methyl)cyclopropane-1-carbonitrile

The title compound was prepared using the procedures described in Example 104A, replacing 1-(bromomethyl)cyclopropanecarbonitrile with 2-bromoacetonitrile. MS (ESI ^- ) m/z 480 (MH) ^- .

Example 100B: 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl )cyclopropane-1-carbonitrile

The title compound was prepared using the procedures described in Example 137B, replacing the compound from Example 100A with the compound from Example 137A. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.13 (br s, 1H), 7.68 (br d, J =8 Hz, 1H), 7.38 (d, J =2Hz, 1H), 7.23(dd, J =8.2Hz, 1H), 7.07(s, 1H), 4.30(s, 2H), 4.11(s, 2H) , 1.35 (t, J =8 Hz, 2H), 1.17 (m, 2H, t, J =8 Hz, 2H); MS (ESI ^- ) m/z 390 (MH) ^- .

Example 101 5-{1-Fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3- ^trione (Compound 200)

In a 20 ml vented tube, the product of Example 1G (0.5 g, 1.075 mmol), cesium carbonate (1.05 g, 3.22 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2', 4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (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). The solids were placed under vacuum for 5 minutes at ambient temperature, then the tube was filled with nitrogen followed by tert -amyl alcohol (10 ml) and isoamylamine (0.25 ml, 2.15 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 31 hours the reaction mixture was cooled to ambient temperature, then extinguished with 1 M hydrochloric acid (5 ml) and diluted with ethyl acetate (5 ml). The aqueous layer was extracted with ethyl acetate (2×5 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (3 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-1-fluoro-7- [(3-methylbutyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 470 [MH] ^- .

To a suspension of crude 5-{3-(benzyloxy)-1-fluoro-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( 0.507 g, 1.075 mmol) and pentamethylbenzene (0.319 g, 2.150 mmol) in dichloromethane (10 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (6.45 ml, 1 M, 6.45 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (5 ml) followed by anhydrous ethanol (5 ml). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 5 ml) then with dichloromethane (2 x 3 ml). The triturated product was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber filter separator. The resulting solution was directly purified by preparative HPLC [5 µm Waters XBridge™ C18 OBD column, 50 x 100 mm, flow rate 100 ml/min, gradient 5-40% methanol in buffer (0.1% trifluoroacetic acid in water by v/v)] in two parts to give the title compound (0.1243 g, 0.326 mmol, 30.3% yield). ¹ H NMR (400 MHz, -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) , 1.72 (dc, J = 13.3, 6.7 Hz, 1H), 1.51 (c, J = 7.1 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H); MS (ESI ^- ) m/z 380 [MH] ^- .

Example 102 5-{1-Fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione (Compound 201)

In a 20 ml vented tube, the product of Example 1G (0.5 g, 1.075 mmol), cesium carbonate (1.05 g, 3.22 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2', 4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (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). The solids were placed under vacuum for 5 minutes at ambient temperature, then the tube was filled with nitrogen followed by tert -amyl alcohol (10 ml) and isobutylamine (0.214 ml, 2.15 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 31 hours the reaction mixture was cooled to ambient temperature, then extinguished with 1 M hydrochloric acid (5 ml) and diluted with ethyl acetate (5 ml). The aqueous layer was extracted with ethyl acetate (2×5 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (3 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-1-fluoro-7- [(2-methylpropyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 456 [MH] ^- .

To a suspension of crude 5-{3-(benzyloxy)-1-fluoro-7-[(2-methylpropyl)amino]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( 0.492 g, 1.075 mmol) and pentamethylbenzene (0.319 g, 2.150 mmol) in dichloromethane (10 ml) at -78°C, a solution of boron trichloride in dichloromethane (6.45 ml, 1 M, 6.45 mmol) was slowly added along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (5 ml) followed by anhydrous ethanol (5 ml). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 5 ml) then with dichloromethane (2 x 3 ml). The triturated product was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber filter separator. The resulting solution was directly purified by preparative HPLC [5 µm Waters XBridge™ C18 OBD column, 50 x 100 mm, flow rate 100 ml/min, gradient 5-40% acetonitrile in buffer (0.1% trifluoroacetic acid in water by vol.)] in three parts to give the title compound (0.0648 g, 0.176 mmol, 16.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.87 (s, 1H), 7.50 (dd, J =9.0, 1.6 Hz, 1H), 7.08 ( dd, J =9.0, 2.3 Hz, 1H), 6.92 (s, 1H), 6.68 (d, J =2.2 Hz, 1H), 4.42 (s, 2H), 2.91 (d, J =6.8 Hz, 2H), 1.97-1.84 (m, 1H), 0.97 (d, J =6.6 Hz, 6H); MS (ESI ^- ) m/z 366 [MH] ^- .

Example 103 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 202)

In a 20 ml vented tube, the product of Example 1G (0.5 g, 1.075 mmol), cesium carbonate (1.05 g, 3.22 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2', 4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (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). The solids were placed under vacuum for 5 minutes at ambient temperature, then the tube was filled with nitrogen followed by tert -amyl alcohol (10 ml) and cyclopropylmethylamine (0.186 ml, 2.15 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 31 hours the reaction mixture was cooled to ambient temperature, then extinguished with 1 M hydrochloric acid (5 ml) and diluted with ethyl acetate (5 ml). The aqueous layer was extracted with ethyl acetate (2×5 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (3 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-7-[(cyclopropylmethyl) amino]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 454 [MH] ^- .

To a suspension of crude 5-{3-(benzyloxy)-7-[(cyclopropylmethyl)amino]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (0.490 g, 1.075 mmol) and pentamethylbenzene (0.319 g, 2.150 mmol) in dichloromethane (10 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (6.45 ml, 1 M, 6.45 mmol) along the wall of the flask so that the internal temperature remained below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (5 ml) followed by anhydrous ethanol (5 ml). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 5 ml) then with dichloromethane (2 x 3 ml). The triturated product was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber filter separator. The resulting solution was directly purified by preparative HPLC [5 µm Waters XBridge™ C18 OBD column, 50 x 100 mm, flow rate 100 ml/min, gradient 5-40% methanol in buffer (0.1% trifluoroacetic acid in water by vol.)] in three parts to give the title compound (0.1252 g, 0.343 mmol, 31.9% yield). ¹ H NMR (400 MHz, -d ₆ ) δ ppm 10.04 (s, 1H), 7.60 (d, J =8.9 Hz, 1H), 7.18 (dd, J =8 .9, 2.2 Hz, 1H), 6.97 (s, 1H), 6.95 (br s, 1H), 4.42 (s, 2H), 3.05 (d, J =6, 8 Hz, 2H), 1.12-1.04 (m, 1H), 0.56-0.45 (m, 2H), 0.32-0.24 (m, 2H); MS (ESI ^- ) m/z 364 [MH] ^- .

Example 104: {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetonitrile (Compound 203 )

Example 104A: 2-((6-(benzyloxy)-7-(1,1-dioxydo-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)oxy)acetonitrile

A mixture of the compound from example 1H (80 mg, 0.2 mmol), 2-bromoacetonitrile (52.8 mg, 0.440 mmol) and cesium carbonate (143 mg, 0.440 mmol) in N,N -dimethylformamide (0.8 ml) was stirred at 75°C for 30 minutes. The mixture was cooled to ambient temperature and filtered. The resulting filtrate was purified by flash column chromatography on silica gel (80 g), eluted with ethyl acetate, then ethyl acetate/methanol (10:1) to give the title compound (50 mg, 0.113 mmol, 56.6% yield). MS (ESI ^- ) m/z 440 (MH) ^- .

Example 104B: {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetonitrile

The title compound was prepared using the procedures described in Example 137B, replacing the compound from Example 104A with the compound from Example 137A. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.52 (br s, 1H), 7.79 (br d, J =8 Hz, 1H), 7.41 (d, J =2Hz, 1H), 7.27(dd, J =8.2Hz, 1H), 7.15(s, 1H), 5.32(s, 2H), 4.48(s, 2H) ; MS (ESI ^- ) m/z 350 (MH) ^- .

Example 105 5-[1-Fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 204)

The title compound was prepared from the compound of Example 1H and 1-bromo-3-methylbutane using the procedures described for Example 83. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.47 (s, 1H), 7.65 (d, J =9.0 Hz, 1H), 7.18 (d, J =2.5 Hz, 1H), 7.12 (dd, J =9.0, 2.5 Hz, 1H), 7.02 (s, 1H), 4.09 (d, J = 7.1 Hz, 4H), 1.81 (dc, J = 13.1, 6.5 Hz, 1H), 1.67 (q, J =6.7 Hz, 2H), 0.95 (d, J =6.6 Hz, 6H); MS (CIAD ^- ) m/z 381.3 (MH) ^- .

Example 106 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 205)

Example 106A: benzyl 3-hydroxy-7-methoxynaphthalene-2-carboxylate

To a solution of 3-hydroxy-7-methoxynaphthalene-2-carboxylic acid (5 g, 22.91 mmol) in N,N -dimethylformamide (50 ml) was added sodium bicarbonate (3.85 g, 45.8 mmol) in order and benzyl bromide (4.09 ml, 34.4 mmol) at 25°C. The mixture was heated to 60°C and stirred for 12 hours at 60°C. The reaction was quenched with water (100 ml). The mixture was extracted with ethyl acetate (3 x 150 ml). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (7 g, 20.43 mmol, 89% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.10 (s, 1 H), 8.40 (s, 1 H), 7.68 (s, 1 H), 7.54 (s, 2 H), 7.43 (brd, J= 7.50 Hz, 4 H), 7.31 (s, 1 H), 7.19-7.24 (m, 1 H), 5.44 (s, 2 H), 3.82 (s, 1 H); MS (ESI ⁺ ) m / z 309 (M+H) ⁺ .

Example 106B: benzyl 3-(acetyloxy)-7-methoxynaphthalene-2-carboxylate

To a solution of the compound from Example 106A (7 g, 20.43 mmol) in dichloromethane (70 mL) were added triethylamine (8.54 mL, 61.3 mmol) and acetyl chloride (4.36 mL, 61.3 mmol) in order at 0°C. The mixture was stirred for 2 hours at 25°C. The reaction was quenched with water (80 ml). The mixture was extracted with dichloromethane (3×200 ml). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (8 g, 20.09 mmol, 98% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.55 (s, 1 H), 7.88 (d, J= 9.04 Hz, 1 H), 7.67 (s, 1 H), 7.60 (d, J= 2.43 Hz, 1 H), 7.47-7.52 (m, 2 H), 7.31-7.46 (m, 4 H), 5 .34 (s, 2 H), 3.88 (s, 3 H), 2.08-2.16 (m, 1 H); MS (ESI ⁺ ) m / z 351 (M+H) ⁺ , 373(M+Na) ⁺ _.

Example 106C: benzyl 3-(acetyloxy)-8-fluoro-7-methoxynaphthalene-2-carboxylate

To a solution of the compound from Example 106B (2 g, 5.02 mmol) in N,N -dimethylformamide (20 mL) was added Selectfluor® (2.135 g, 6.03 mmol) at 0°C. The mixture was stirred for 12 hours at 25°C. The reaction was quenched with saturated aqueous sodium thiosulfate (100 ml, 1 M). The mixture was extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with brine (500 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (1 g, 2.308 mmol, 45.9% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.56 (s, 1 H), 7.75-7.87 (m, 3 H), 7.39-7.51 (m , 6 H), 5.36 (s, 2 H), 4.00 (s, 3 H), 2.13 (s, 1 H).

Example 106D: 8-fluoro-3-hydroxy-7-methoxynaphthalene-2-carboxylic acid

To a solution of the compound from example 106C (2 g, 4.89 mmol) in tetrahydrofuran (10 ml), methanol (10 ml) and water (5 ml) was added sodium hydroxide (0.586 g, 14.66 mmol) at 25°C. The mixture was heated to 70°C and stirred for 3 hours at 70°C. The mixture was stirred at 70°C for another 3 hours. One additional 770 mg tube was prepared and reacted as described above. The reaction mixtures were combined and concentrated under reduced pressure to remove most of the tetrahydrofuran and methanol. Then the residue was diluted with water, and the resulting mixture was acidified with aqueous hydrochloric acid (1 M) to pH=3. A solid precipitated and was collected by filtration. The solid was dried under high vacuum to give the title compound (1.4 g, 5.33 mmol, 81.2% yield). MS (ESI ^- ) m / z 235 (MH) ^- .

Example 106E: benzyl 3-(benzyloxy)-8-fluoro-7-methoxynaphthalene-2-carboxylate

To a solution of the compound from example 106D (1.4 g, 5.33 mmol) in N,N -dimethylformamide (15 ml) was added cesium carbonate (Cs ₂ CO _3, 5.21 g, 16.00 mmol) at 25°C and stirred the mixture for 5 minutes at 25°C. Benzyl bromide (1.396 ml, 11.74 mmol) was added to the mixture at 25°C. The reaction was heated to 70°C and stirred for 12 hours at 70°C. The mixture was then poured into ice water (100 ml) and stirred for 30 minutes. A solid precipitated out. The solid was collected by filtration and dried under high vacuum to give the title compound (2.3 g, 4.69 mmol, 88% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.25 (s, 1 H), 7.70 (s, 1 H), 7.59-7.67 (m, 2 H) , 7.46-7.51 (m, 2 H), 7.34 (br. l, J= 2.20 Hz, 8 H), 5.34-5.39 (m, 2 H), 5, 26 (s, 2 H), 3.89-4.00 (m, 1 H); MS (ESI ⁺ ) m / z 417, 439 (M+H, M+Na) ⁺ .

Example 106F: 3-(benzyloxy)-8-fluoro-7-methoxynaphthalene-2-carboxylic acid

To a solution of the compound from example 106E (2.3 g, 4.69 mmol) in tetrahydrofuran (10 ml), methanol (10 ml) and water (5 ml) was added sodium hydroxide (0.376 g, 9.39 mmol) at 25° C. The mixture was heated to 60°C and stirred for 3 hours at 60°C. The reaction mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran and methanol. The residue was diluted with water (30 ml), and the resulting mixture was acidified with aqueous hydrochloric acid (1 M) to pH=3. A solid precipitated out. The mixture was filtered and the solid was collected and dried under high vacuum to give the title compound (1.8 g, 4.69 mmol, 100% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.03 (s, 1 H), 7.63 (s, 1 H), 7.48-7.58 (m, 4 H) , 7.40 (s, 2 H), 7.32 (s, 1 H), 5.24 (s, 2 H), 3.90-3.98 (m, 1 H); MS (ESI ^- ) m / z 325 (MH) ^- .

Example 106G: tert-butyl [3-(benzyloxy)-8-fluoro-7-methoxynaphthalen-2-yl]carbamate

To a solution of the compound from Example 106F (1.8 g, 4.69 mmol) in toluene (10 mL) and t -butanol (10 mL) was added diphenylphosphoryl azide (1.935 g, 7.03 mmol) and triethylamine (1.307 mL, 9. 38 mmol) at 25°C, heated the mixture to 110°C and stirred for 3 hours at 110°C under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (1.4 g, 3.17 mmol, 67.6% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.33 (s, 1 H), 8.10 (s, 1 H), 7.52-7.59 (m, 3 H) , 7.32-7.48(m, 5H), 5.28(s, 2H), 3.91(s, 1H), 1.49(s, 9H); MS (ESI ⁺ ) m / z 298, 342 (M-99, M-55) ⁺ .

Example 106H: 3-(benzyloxy)-8-fluoro-7-methoxynaphthalene-2-amine

Trifluoroacetic acid (3 ml) was added dropwise to a solution of the compound from Example 106G (1.4 g, 3.17 mmol) in dichloromethane (12 ml) at 0°C. The mixture was stirred for 30 minutes at 25°C. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (5 ml). The mixture was adjusted to pH=8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1 g, 3.03 mmol, 95% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.54 (s, 2 H), 7.31-7.44 (m, 4 H), 7.26 (s, 1 H) , 7.02-7.08 (m, 1 H), 6.96 (s, 1 H), 5.42 (s, 2 H), 5.22 (s, 2 H), 3.86 (s , 1H); MS (ESI ⁺ ) m / z 298 (M+H) ⁺ .

Example 106I: methyl {[3-(benzyloxy)-8-fluoro-7-methoxynaphthalen-2-yl]amino}acetate

To a solution of the compound from example 106H (1 g, 3.03 mmol) in N,N -dimethylformamide (10 ml) were added in order methyl bromoacetate (0.418 ml, 4.54 mmol) and potassium carbonate (K ₂ CO _3, 0.837 g, 6.05 mmol) at 25°C. The mixture was heated to 65°C and stirred for 4 hours at 65°C. More methyl bromoacetate (0.279 ml, 3.03 mmol) and potassium carbonate (K ₂ CO ₃ 0.418 g, 3.03 mmol) were added at 65°C and the mixture was stirred for an additional 4 hours at 65°C. The mixture was then poured into ice water (50 ml) and stirred for 30 minutes. The mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (500 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (900 mg, 2.071 mmol, 68.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.56 (d, J= 7.02 Hz, 2 H), 7.40-7.46 (m, 3 H), 7, 32 (d, J= 1.32 Hz, 2 H), 7.11 (s, 1 H), 6.56 (s, 1 H), 5.93 (s, 1 H), 5.27 (s , 2 H), 4.12 (d, J= 6.14 Hz, 2 H), 3.88 (s, 3 H), 3.68 (s, 1 H); MS (ESI ⁺ ) m / z 370 (M+H) ⁺ .

Example 106J: methyl {[3-(benzyloxy)-1,8-difluoro-7-methoxynaphthalen-2-yl]amino}acetate

To a solution of the compound from Example 106I (900 mg, 2.071 mmol) in N,N -dimethylformamide (10 mL) was added dropwise a solution of 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane, ditetrafluoroborate (Selectfluor®, 807 mg, 2.278 mmol) in N,N -dimethylformamide (2 ml) at 0°C. The mixture was stirred for 5 minutes at 0°C. The reaction was quenched with aqueous sodium thiosulfate (50 ml, 1 M) and stirred for 10 minutes at 25°C. The mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (500 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (320 mg, 0.743 mmol, 35.9% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.47-7.56 (m, 3 H), 7.40-7.46 (m, 2 H), 7.36 (s , 1 H), 7.20-7.26 (m, 2 H), 5.56 (br s, 1 H), 5.26 (s, 2 H), 4.21 (br d, J = 2.69 Hz, 2 H), 3.89 (s, 3 H), 3.63 (s, 1 H); MS (ESI ⁺ ) m / z 388 (M+H) ⁺ .

Example 106K: methyl {[3-(benzyloxy)-1,8-difluoro-7-methoxynaphthalen-2-yl][(t-butoxycarbonyl)sulfamoyl]amino}acetate

To a solution of chlorosulfonyl isocyanate (141 mg, 0.999 mmol) in dichloromethane (10 ml) was added dropwise a solution of tert -butanol (0.096 ml, 0.999 mmol) in dichloromethane (3 ml) at 25°C and the mixture was stirred for 30 minutes at 25°C. C. Then, a solution of the compound from Example 106J (215 mg, 0.500 mmol) and triethylamine (0.209 ml, 1.499 mmol) in dichloromethane (10 ml) at 25° C. was added dropwise, and the resulting mixture was stirred for 1 hour at 25 °C. The reaction was quenched with water (20 ml). The mixture was extracted with methylene dichloride (3×100 ml). The combined organic layers were washed with brine (300 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (300 mg), which was used for the next step without further purification. MS (ESI ⁺ ) m / z 467, 511, 589 (M-99, M-55, M+Na) ⁺ .

Example 106L: methyl {[3-(benzyloxy)-1,8-difluoro-7-methoxynaphthalen-2-yl](sulfamoyl)amino}acetate

To a solution of the compound from example 106K (300 mg, 0.477 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (1 ml) at 0°C. The mixture was stirred for 30 minutes at 25°C. The reaction mixture was concentrated under reduced pressure. The reaction residue was then diluted with ethyl acetate (1 ml) and the resulting mixture was made basic with saturated sodium bicarbonate solution to pH=8. The mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (200 ml), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (220 mg, 0.401 mmol, 84% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.65-7.70 (m, 1 H), 7.57 (brd, J= 7.89 Hz, 3 H), 7.32-7.45(m, 4H), 7.08(s, 2H), 5.24(s, 2H), 4.44-4.51(m, 1H), 4, 29-4.35(m, 1H), 3.94(s, 1H), 3.56(s, 3H), 1.23(s, 2H); MS (ESI ⁺ ) m / z 467, 489 (M+H, M+Na) ⁺ .

Example 106M: 5-[3-(benzyloxy)-1,8-difluoro-7-methoxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from example 106L (50 mg, 0.086 mmol) in tetrahydrofuran (2 ml) was added sodium methoxide (49.2 mg, 0.273 mmol) at 25°C and the mixture was stirred for 2 hours at 25°C. One additional 20 mg tube and one additional 150 mg tube were prepared and reacted as described above. All mixtures were acidified with aqueous hydrochloric acid (1 M) to pH=3 and combined. The resulting mixture was extracted with ethyl acetate (3 x 200 ml). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (280 mg, 0.516 mmol, 90% yield), which was used for the next step without further purification. MS (ESI ^- ) m / z 433 (MH) ^- .

Example 106N: 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from example 106M (250 mg, 0.460 mmol) in methylene chloride (3 ml) was added boron trichloride (2.302 ml, 2.302 mmol, 1 M in dichloromethane) at -70°C, and then the mixture was stirred for 4 hours at - 70°C. The reaction was quenched with methyl alcohol (5 ml) and concentrated under reduced pressure. The residue was purified by preparative HPLC [HuaPu C8 Extreme BDS 150×30 mm, 5 µm column, flow rate 25 ml/min, 20-40% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] and lyophilized to give the title compound (85 mg, 0.237 mmol, 51.5% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.77-9.92 (m, 1 H), 7.55 (s, 1 H), 7.50 (d, J= 7 .95 Hz, 1 H), 7.06 (s, 1 H), 7.01-7.10 (m, 1 H), 4.08 (s, 2 H), 3.92 (s, 1 H ); ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ ppm -121.53, 112.68 (1F), 143.3, 143.4 (1F); MS (IER ^- ) m / z 343 (MH) ^-

Example 107 5-{7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trione (Compound 206)

The compound from Example 1G (100 mg, 0.215 mmol, 1.0 eq.) and SPhos Pd G4 (8.54 mg, 10.75 μmol, 0.05 eq.) were combined in N,N -dimethylacetamide (2 ml). (1-( tert -Butoxycarbonyl)azetidin-3-yl)zinc(II)iodide (74.9mg, 0.215mmol, 1.0eq., 0.18M in tetrahydrofuran) was added), the reaction was purged with N ₂ , stoppered and heated to 65°C overnight.

The reaction mixture was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give t -butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]azetidine-1-carboxylate (80 mg, 69% yield. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.88-7.81 (m, 2H), 7.60-7.54 (m, 3H), 7.41-7.28 (m, 4H), 5.26 (s, 2H), 4.33-4.30 (m, 2H), 4.10 (s, 2H), 4.04-3.95 (m, 1H), 3.93-3.90 (m, 2H), 1.42 (s, 9H); MS (ESI ^- ) m/z 540.1 (MH) ⁺ .

The residue was dissolved in 1 dichloromethane (1 ml), trifluoroacetic acid (100 μl) was added and stirred until the tert -butoxycarbonyl group was completely removed. The volatiles were removed in a stream of nitrogen to give 5-[7-(azetidin-3-yl)-3-(benzyloxy)-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione trifluoroacetate, which was used directly in the next step.

5-[7-(azetidin-3-yl)-3-(benzyloxy)-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione trifluoroacetate (50 mg, 0 .11 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (1.0 ml). N -ethyl- N -isopropylpropan-2-amine (59 μl, 0.34 mmol, 3.0 eq.) was added, followed by cyclopropanesulfonyl chloride (14 μl, 0.14 mmol, 1.3 eq.). The reaction mixture was stirred overnight at ambient temperature. The reaction was filtered and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give 5-{ 3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (31.7 mg, 51% yield.

5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( 31.7 mg, 0.058 mmol) and tetrahydrofuran (2 ml) were added in 5% Pd/C (wet JM#9) (13.27 mg, 0.058 mmol) in a 20 ml Barnstead Hast C reactor and stirred for 60.1 hours at 60 psi inch of hydrogen and 25°C. The reaction mixture was filtered and the solvent was removed under a stream of nitrogen. The mixture was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (16.5 mg, 62% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.90-7.85 (m, 1H), 7.84-7.77 (m, 1H), 7.58 (dd, J = 8.7, 1.8 Hz, 1H), 7.13 (s, 1H), 4.38-4.29 (m, 2H), 4.18 (s, 2H), 4.12-4, 07 (m, 3H), 2.92-2.81 (m, 1H), 1.22-1.08 (m, 2H), 1.08-0.99 (m, 2H); MS (APCI ⁺ ) m/z 473.2 (M+H ₂ O) ⁺ .

Example 108: 5-{7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trione (Compound 207)

Example 108 was prepared using the procedure described in Example 107, replacing cyclopropylcarbonyl chloride with cyclopropanesulfonyl chloride, to give 5-{3-(benzyloxy)-7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoronaphthalene -2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (35.6 mg, 62% yield).

5-{3-(benzyloxy)-7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione ( 35.6 mg, 0.070 mmol) and tetrahydrofuran (2 ml) were added in 5% Pd/C (wet JM#9) (15.96 mg, 0.070 mmol) in a 20 ml Barnstead Hast C reactor and stirred for 33 hours at 50 psi inch of hydrogen and 25°C. The reaction mixture was filtered and the solvent was removed under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (15.9 mg, 54% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.85 (s, 1H), 7.84-7.76 (m, 1H), 7.57 (dd, J =8.6 , 1.8 Hz, 1H), 7.13 (s, 1H), 4.76 (t, J =8.7 Hz, 1H), 4.41-4.33 (m, 2H), 4.18 (s, 2H), 4.14-4.05 (m, 1H), 3.96 (dd, J =9.6, 6.1 Hz, 1H), 1.73-1.60 (m, 1H ), 0.87-0.74 (m, 4H); MS (APCI ⁺ ) m/z 420.2 (M+H) ⁺ .

Example 109: (2 E )-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] prop-2-ennitrile (Compound 208)

Example 109A: 3-(6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)acrylonitrile

A mixture of the compound from Example 1G (233 mg, 0.5 mmol), acrylonitrile (133 mg, 2.500 mmol), 2 - dicyclohexylphosphino - 2 ′, 6′ - dimethoxybiphenyl (45.2 mg, 0.110 mmol), potassium carbonate (207 mg , 1.500 mmol) and palladium (II) acetate (12.35 mg, 0.055 mmol) in N,N -dimethylformamide (0.6 ml) were filled with N ₂ and heated to 130°C for 40 minutes. The mixture was diluted with ethyl acetate (50 ml) and washed with 0.5 N aqueous HCl (10 ml × 2) and brine (10 ml). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (80 g), eluted with ethyl acetate/methanol (0 to 10%) to give the title compound (140 mg, 0.32 mmol, 64% yield). MS (ESI ^- ) m/z 436 (MH) ^- .

Example 109B: (2E)-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]prop -2-ennitrile

The title compound was prepared using the procedures described in Example 137B, replacing the compound from Example 109A with the compound from Example 137A. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 11.02 (br s, 1H), 8.36 (d, J =2 Hz, 1H), 8.02 (dd, J = 8, 2, 1H), 7.89 (bd, J = 8 Hz, 1H), 7.56 (d, J = 12 Hz, 1H), 7.19 (s, 1H), 5.92 ( e, J =12 Hz, 1H), 4.46 (s, 2H); MS (ESI ^- ) m/z 348 (MH) ^- .

Example 110 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 209)

The product from Example 140 (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 Barnstead Hastelloy C reactor. The mixture was allowed to stir for 86 hours in hydrogen atmosphere (158 psi) at 25°C. The reaction mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated to give the crude title compound, which was purified by reverse phase HPLC (Phenomenex® C8(2) Luna® 5 μm AXIA™ 150 x 30 mm column, 3-100% gradient of acetonitrile (A) and 10 mM acetate ammonium in water (B) for 17 minutes at a flow rate of 50 ml/minute) to give the title compound (0.013 g, 27% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 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 (CIAD ^- ) m/z 367 [MH] ^- .

Example 111: 5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3-trione ( Connection 210)

The title compound was prepared from the compound of Example 1H and 2-(bromomethyl)-1,1-difluoropropane using the procedures described for Example 83. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.65 (dd, J =9.0, 1.5 Hz, 1H), 7.20-7.06 (m, 2H), 7.00 (d, J =1.4 Hz, 1H), 4.24 ( ddd, J = 10.0, 6.4, 3.2 Hz, 1H), 4.05 (s, 2H), 4.09-3.99 (m, 1H), 2.23 (dtt, J = 15.8, 8.2, 5.2 Hz, 1H), 1.77-1.63 (m, 1H), 1.49 (dtd, J = 13.6, 7.7, 4.2 Hz, 1H); MS (CIAD ^- ) m/z 401.3 (MH) ^- .

Example 112 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 211)

Example 112A: 5-[3-(benzyloxy)-7-(2-cyclopropylethoxy)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A mixture of the product of example 1H (95 mg, 0.24 mmol), 2-bromoethylcyclopropane (70 mg, 0.47 mmol) and cesium carbonate (64 mg, 0.35 mmol) in N,N -dimethylformamide (1 ml) was stirred at ambient temperature for 14 hours. The reaction mixture was concentrated and the residue was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ (50 mm × 30 mm) column with a gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) at a flow rate of 40 ml/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compound. MS (HIAD ⁺ ) m/z 488.1 (M+NH ₄ ) ⁺ .

Example 112B: 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from Example 112A (93 mg, 0.20 mmol) in tetrahydrofuran (2 mL) was added 5% Pd/C (wet JM#9) (29.4 mg, 0.129 mmol). The mixture was stirred in a 2 ml high pressure tube with 150 psi hydrogen. inch within 18 hours. The reaction mixture was concentrated and the residue was purified by reverse-phase preparative HPLC on a 5 μm Waters XBridge™ C8 column (75 mm × 30 mm) with a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) ( 0-0.5 minutes 15% A, 0.5-8.0 minutes linear gradient 15-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100- 15% A, 9.1-10.0 minutes 15% A) at a flow rate of 40 ml/minute to give the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.67-7.60 (m, 1H), 7.19-7.09 (m, 2H), 7.02 (s, 1H ), 4.14-4.06 (m, 4H), 1.65 (k, J = 6.6 Hz, 2H), 0.90-0.79 (m, 1H), 0.47-0, 37 (m, 2H), 0.21-0.06 (m, 2H); MS (ESI ^- ) m / z 379.0 (MH) ^- .

Example 113 5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3-trione (Compound 212 )

The title compound was prepared from the compound of Example 1H and ((2-bromoethoxy)methyl)cyclopropane a using the methods described for Example 112. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.65 (dd, J =9.1, 1.4 Hz, 1H), 7.19 (d, J =2.6 Hz, 1H), 7.15 (dd, J =9.0, 2.6 Hz, 1H), 7.02 (s, 1H), 4.19-4.14 (m, 2H), 4.12 (s, 2H), 3.30 (d, J = 6.8 Hz, 2H), 1.04-0.94 (m, 1H), 0.49-0.41 (m, 2H), 0.19-0.12 (m, 2H); MS (ESI ^- ) m / z 409.0 (MH) ^- .

Example 114: 5-{1-Fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione (Compound 213)

The title compound was prepared from the compound of Example 1H and 2-(2-bromoethyl)oxolane using the methods described for Example 112. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.70 (dd , J =9.0, 1.4Hz, 1H), 7.24-7.15(m, 2H), 7.08(s, 1H), 4.18(m, 4H), 4.00( m, 1H), 3.68 (m, 1H), 2.10-1.80 (m, 5H), 1.55 (m, 1H), ); MS (ESI ⁺ ) m / z 411.3 (M+H) ⁺ .

Example 115 5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3-trione (Compound 214 )

The title compound was prepared from the compound of Example 1H and (2-bromoethoxy)cyclobutane using the methods described for Example 112. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.65 (dd, J =9.0, 1.5 Hz, 1H), 7.24-7.08 (m, 2H), 7.02 (d, J =1.3 Hz, 1H), 4.24-4.08 ( m, 4H), 4.03-3.88 (m, 1H), 3.68-3.59 (m, 2H), 2.14 (m, 2H), 1.99-1.74 (m, 2H), 1.61 (m, 1H), 1.52-1.23 (m, 1H); MS (ESI ^- ) m / z 408.8 (MH) ^- .

Example 116: 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione (Compound 215)

The title compound was prepared from the compound of Example 1H and 2-(2-bromoethoxy)propane using the methods described for Example 112. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.70 (dd , J =9.1, 1.4Hz, 1H), 7.24(d, J =2.6Hz, 1H), 7.20(dd, J =9.0, 2.6Hz, 1H) , 7.08 (s, 1H), 4.19 (m, 4H), 3.79-3.75 (m, 2H), 3.73-3.63 (m, 1H), 1.16 ( e, J =6.1 Hz, 6H); MS (ESI ^- ) m / z 397.0 (MH) ^- .

Example 117 5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 216)

The title compound was prepared from the compound of Example 1H and 1-bromo-3-ethoxypropane using the methods described for Example 112. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.70 (dd, J = 9.0, 1.4 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 7.19 (dd, J = 9.0, 2.5 Hz, 1H), 7.08 (s, 1H), 4.22-4.09 (m, 4H), 3.58 (t, J = 6.3 Hz, 2H), 3.48 (k, J = 7.0 Hz , 2H), 2.03 (t, J =6.3 Hz, 2H), 1.15 (t, J =7.0 Hz, 3H); MS (ESI ^- ) m / z 396.9 (MH) ^- .

Example 118 5-[7-(2- tert -butoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 217)

The title compound was prepared from the compound of Example 1H and 2-(2-bromoethoxy)-2-methylpropane using the methods described for Example 112. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7, 70 (dd, J =8.9, 1.4 Hz, 1H), 7.25 (d, J =2.5 Hz, 1H), 7.19 (dd, J =9.0, 2.5 Hz , 1H), 7.08 (s, 1H), 4.17 (m, 4H), 3.76-3.65 (m, 2H), 1.21 (s, 9H); MS (ESI ^- ) m / z 410.9 (MH) ^- .

Example 119 _ _ _ _ _ ^_ _ 1,1,3-trione (Compound 218)

The title compound was prepared from the compound of Example 1H and rac-(1 R ,2 R )-1-(bromomethyl)-2-ethylcyclopropane using the methods described for Example 112. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.76-7.65 (m, 1H), 7.24-7.12 (m, 2H), 7.07 (s, 1H), 4.17 (s, 2H), 3.96 (dd, J =7.0, 3.5 Hz, 2H), 1.40-1.21 (m, 2H), 1.03 (dt, J =8.2, 4.5 Hz, 1H), 0.96 (t, J =7.3 Hz, 3H), 0.79 (dt, J =8.1, 5.0 Hz, 1H), 0.55 (dt, J =8.8 , 4.6 Hz, 1H), 0.43 (dt, J =8.2, 4.8 Hz, 1H); MS (ESI ^- ) m / z 410.9 (MH) ^- .

Example 120 5-[1-Fluoro-3-hydroxy-7-(4-methylpentyl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 219)

The product from Example 141 (0.0506 g, 0.134 mmol) and trifluoroethanol (2 mL) were added to 10% Pd/C, dry (0.0145 g, 0.134 mmol) in a 20 mL Barnstead Hastelloy C reactor. The mixture was allowed to stir for 86 hours in a hydrogen atmosphere (158 psi) at 25°C. The reaction mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated to give the crude title compound, which was purified by reverse phase HPLC (Phenomenex® C8(2) Luna® 5 μm AXIA™ 150 x 30 mm column, 3-100% gradient of acetonitrile (A) and 10 mM acetate ammonium in water (B) for 17 minutes at a flow rate of 50 ml/minute to give the title compound as the ammonium salt (0.0154 g, 30%) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.64 (s, 1H), 7.69-7.60 (m, 2H), 7.34 (dd, J =8.4, 1.7 Hz, 1H), 7.21 ( s, 1H), 7.09 (s, 1H), 7.03 (d, J = 1.4 Hz, 1H), 6.96 (s, 1H), 4.10 (s, 2H), 2, 70 (t, J = 7.6 Hz, 2H), 1.69-1.59 (m, 2H), 1.55 (dc, J = 13.2, 6.8 Hz, 1H), 1.26 -1.14 (m, 2H), 0.85 (d, J = 6.6 Hz, 6H), MS (APCI ^- ) m/z 379 [MH] ^- .

Example 121: 5-{7-[3-(2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5 ^- thiadiazolidin-1, 1,3-trione (Compound 220)

In a 4 ml tube were combined the product of example 1G (0.100 g, 0.215 mmol), cesium carbonate (0.210 g, 0.645 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-( 2′-amino-1,1′-biphenyl)]palladium (II) methanesulfonate (RuPhos Pd G3 precatalyst, 0.0054 g, 0.0065 mmol) and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos, 0.003 g, 0.0065 mmol). The solids were placed under vacuum for 5 minutes at ambient temperature, then the tube was filled with nitrogen followed by tert -amyl alcohol (2 mL) and 3-(2,2-dimethylpropyl)pyrrolidine (0.74 mL, 0.43 mmol ). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 16 hours the reaction mixture was cooled to ambient temperature, then extinguished with 1 M hydrochloric acid (2 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-7-[3-( 2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 524 [MH] ^- .

To a suspension of crude 5-{3-(benzyloxy)-7-[3-(2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione (0.113 g, 0.215 mmol) and pentamethylbenzene (0.064 g, 0.430 mmol) in dichloromethane (2 mL) a solution of boron trichloride in dichloromethane (1.29 mL, 1 M, 1 .29 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml) followed by anhydrous ethanol (1 ml). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 3 ml), then dissolved in dimethyl sulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 µm 100Å AXIA™ (30 mm × 75 mm) column with a gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at flow rate 50 ml/minute (0-1.0 minutes 5% A, 1.0-8.5 minutes linear gradient 5-100% A, 8.5-11.5 minutes 100% A, 11.5-12.0 minutes linear gradient 95-5% A) to give the title compound as ammonium salt (0.0434 g, 0.0.096 mmol, 44.6% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.57 (dd, J =9.1, 1.7 Hz, 1H), 7.00 (dd, J =9.1, 2 .4 Hz, 1H), 6.92 (d, J =1.3 Hz, 1H), 6.59 (d, J =2.4 Hz, 1H), 4.08 (s, 2H), 3, 60-3.51 (m, 2H), 3.42-3.25 (m, 2H), 2.89 (t, J =9.1 Hz, 1H), 2.41-2.28 (m, 1H), 2.24-2.12 (m, 1H), 1.63 (dc, J = 11.6, 9.1 Hz, 1H), 1.43 (d, J = 6.1 Hz, 2H ), 0.95 (s, 9H); MS (ESI ^- ) m/z 434 [MH] ^- .

Example 122: 5-[7-(1-Chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione (Compound 221)

Example 122A: 5-[3-(Benzyloxy)-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl]-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione

Mixture of the compound from Example 1G (326 mg, 0.7 mmol), 1,1' - bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (28.6 mg, 0.035 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (284 mg, 1.120 mmol) and potassium acetate (206 mg, 2.100 mmol) in N , N -dimethylformamide (3.5 ml) was purged with nitrogen for 5 minutes, and then heated to 100°C for 3 hours. The mixture was cooled to ambient temperature and diluted with dichloromethane (50 ml). The organic phase was washed with an aqueous solution of 0.1 N HCl (15 ml), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (40 g) and eluted with dichloromethane/methanol (0 to 10%) to give the title compound (250 mg, 0.488 mmol, 69.7% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.26 (s, 1H), 7.82 (brd, J =8 Hz, 1H), 7.74 (m, 1H) , 7.57 (m, 2H), 7.37 (m, 3H), 7.32 (m, 1H), 5.28 (s, 2H), 4.10 (s, 2H), 1.34 ( s, 12H); MS (ESI ^- ) m/z 511 (MH) ^- .

Example 122B: 5-[3-(Benzyloxy)-1-fluoro-7-(oxetan-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Mixture of the compound from Example 122A (208 mg, 0.405 mmol), sodium bis(trimethylsilyl)amide (89 mg, 0.486 mmol), trans -2-aminocyclohexanol hydrochloride (6.14 mg, 0.041 mmol), and nickel (II) iodide (12 .66 mg, 0.041 mmol) in isopropanol (1 ml) was purged with nitrogen for 25 minutes, then 3-iodooxetane (49.7 mg, 0.27 mmol) in isopropanol (0.5 ml) was added. The mixture was heated to 120°C for 1.5 hours, then cooled to ambient temperature, diluted with dichloromethane (50 ml) and washed with 0.1 N aqueous HCl (15 ml). The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (80 g), eluted with ethyl acetate/methanol (0 to 10%) to give the title compound (30 mg, 0.068 mmol, 25.1% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.88 (br s, 1H), 7.86 (br d, J =8 Hz, 1H), 7.65 (dd, J =8, 2Hz, 1H), 7.56(m, 2H), 7.35(m, 4H), 5.26(s, 2H), 5.01(dd, J =8, 14Hz, 2H )), 4.77 (dd, J =8, 14 Hz, 2H)), 4.44 (m, 1H), 4.09 (s, 2H); MS (ESI ^- ) m/z 441 (MH) ^- .

Example 122C: 5-[7-(1-Chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione

Trichloroborane (0.678 ml , 0.678 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 1 hour and then at 0°C for 30 minutes. The mixture was quenched with ethanol (3 ml), stirred at 0°C for 5 minutes and concentrated. The solid was washed with heptane (4 x 2 ml) and dichloromethane (4 x 2 ml) and concentrated to give the title compound (17 mg, 0.044 mmol, 97% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.58 (br s, 1H), 7.78 (s, 1H), 7.73 (br d, J =8, 1H ), 7.48 (dd, J =8, 2, 1H), 7.11 (s, 1H), 4.47 (s, 2H), 4.05 (m, 1H), 3.97(m, 1H), 3.71 (d, J =8, 2H), 3.23 (m, 1H); MS (ESI ^- ) m/z 387 (MH) ^- .

Example 123: 5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3- trione (Compound 222)

Example 123A: tert-Butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] -2,5-dihydro-1H-pyrrole-1-carboxylate

A microwave tube was filled with the compound from Example 1G (4 g, 8.60 mmol), t -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), tetrakis(triphenylphosphine)palladium (0) (497 mg, 0.43 mmol) and sodium carbonate (1 M, 12, 90 ml, 25.8 mmol). Thereafter, 1,4-dioxane (4 ml) was added and the reaction mixture was purged with nitrogen for 5 minutes, after which it was heated to 90° C. overnight. After cooling, the mixture was partitioned between water (5 ml) and ethyl acetate (5 ml) and the aqueous layer was further extracted with ethyl acetate. The combined organic fractions were concentrated under reduced pressure and the residue was subjected to column chromatography (SiO ₂ , dry diatomaceous earth load, 10% methanol in dichloromethane) to give the title compound (3.75 g, 6.77 mmol, 79% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.86-7.78 (m, 2H), 7.78-7.71 (m, 1H), 7.59-7.53 (m, 2H), 7.41-7.33 (m, 3H), 7.35-7.28 (m, 1H), 6.54 (dt, J =15.2, 2.1 Hz, 1H ), 5.27 (s, 2H), 4.53 (dd, J =9.3, 4.7 Hz, 2H), 4.26 (d, J =11.7 Hz, 2H), 4.10 (s, 2H), 1.47 (d, J =10.7 Hz, 9H); MS (CIAD ^- ) m/z 552 [MH] ^- .

Example 123B: tert-butyl 3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidin- 1-carboxylate

Example 123A (2.76 g, 4.99 mmol) and tetrahydrofuran (10 mL) were added in 5% Pd/C (wet) (2.8 g, 12.26 mmol) in a 20 mL Barnstead Hast C reactor and stirred at 25°C for 68 hours at 61 psi. inch of hydrogen gas. After filtration on diatomite, the filtrate was concentrated under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0 1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (1.7 g, 3.65 mmol, 73% 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 (CIAD ^- ) m/z 464 [MH] ^- .

Example 123C: 5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 , ^2,5 -thiadiazolidin-1,1,3- trion

The product from example 123B (100 mg, 0.21 mmol), methylene chloride (2 ml) and trifluoroacetic acid (2 ml) were added to a 50 ml round bottom flask at ambient temperature. The reaction mixture was stirred for 30 minutes at ambient temperature. The volatiles were removed under reduced pressure and the residue was taken to the next step without purification. MS (CIAD ⁺ ) m/z 366 [M+H] ⁺

A 20 ml microwave tube was filled with the trifluoroacetic acid salt of crude 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trione and sodium carbonate (58.0 mg, 0.547 mmol). Then N,N -dimethylformamide (3 ml) was added and the mixture was stirred at ambient temperature for 5 minutes. Thereafter, cyclopropanecarbaldehyde (57.5 mg, 0.821 mmol) and acetic acid (0.078 ml, 1.368 mmol) were added and the mixture was stirred for 5 minutes at room temperature. Sodium cyanoborohydride (103 mg, 1.642 mmol) was then added. The mixture was stirred at ambient temperature for two hours. The reaction was partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was extracted with additional ethyl acetate (2×3 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (5 ml) and dried over sodium sulfate. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (15 mg, 0.036 mmol, 17% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.75 (s, 1H), 7.76 (d, J =1.7 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.6, 1.8 Hz, 1H), 7.00 (s, 1H), 4.04 (s, 2H), 3.84- 3.71(m, 1H), 3.70-3.57(m, J =9.4Hz, 1H), 3.49(s, 2H), 3.53-3.35(m, 3H) , 3.06 (dd, J =7.3, 2.6 Hz, 2H), 2.42-2.35 (m, 1H), 2.12-2.01 (m, 1H), 1.10 -0.99 (m, 1H), 0.61-0.50 (m, 2H), 0.37-0.25 (m, 2H); MS (CIAD ^- ) m/z 418 [MH] ^- .

Example 124 5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 223)

Example 124A: 5-[3-(benzyloxy)-7-(cyclopropyloxy)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To the product of Example 1H (300 mg, 0.746 mmol) in N,N -dimethylformamide (2 mL) was added cesium carbonate (534 mg, 1.640 mmol) and bromocyclopropane (1.2 mL, 14.91 mmol). The mixture was heated to 130° C. overnight. After cooling, the reaction mixture was filtered and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (40 mg, 0.090 mmol, 12% yield) . MS (CIAD ^- ) m/z 441 [MH] ^- .

Example 124B: 5 - [7 - (cyclopropyloxy) - 1 - fluoro - 3 - hydroxynaphthalene - 2 - yl] - 1 λ ⁶ ,2,5 - thiadiazolidin - 1,1,3 - trione

A 250 ml round bottom flask was filled with nitrogen followed by the addition of 5% Pd/C (35 mg, 0.329 mmol) and tetrahydrofuran (10 ml). Then a solution of the compound from example 124A (40 mg, 0.083 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. The filtrate was concentrated under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (12 mg, 0.034 mmol, 10.36% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.60 (dd, J =9.0, 1.4 Hz, 1H), 7.38 (d, J =2.5 Hz, 1H), 7.06 (dd, J =9.0, 2.5 Hz, 1H), 6.97 (s, 1H), 4.05 (s, 2H), 3.89 (tt, J =6 .0, 2.9 Hz, 1H), 0.78 (dt, J = 7.3, 5.6 Hz, 2H), 0.67-0.60 (m, 2H); MS (CIAD ^- ) m/z 351 [MH] ^- .

Example 125 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione (Compound 224 )

In a 4 ml tube were combined the product of Example 1G (0.150 g, 0.322 mmol), cesium carbonate (0.315 g, 0.967 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i -propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (BrettPhos Pd G3 precatalyst, 8.8 mg, 9.7 µmol) and 2- (dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, 5.2 mg, 9.7 µmol). The solids were placed under vacuum for 5 minutes at ambient temperature, then the tube was filled with nitrogen followed by tert -amyl alcohol (3 ml) and 2-cyclopropylethylamine (0.061 ml, 0.65 mmol). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 16 hours the reaction mixture was cooled to ambient temperature, then extinguished with 1 M hydrochloric acid (3 ml) and diluted with ethyl acetate (3 ml). The aqueous layer was extracted with ethyl acetate (2×3 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (3 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-7-[(2- cyclopropylethyl)amino]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 468 [MH] ^- .

To a suspension of crude 5-{3-(benzyloxy)-7-[(2-cyclopropylethyl)amino]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (0.151 g, 0.322 mmol) and pentamethylbenzene (0.064 g, 0.430 mmol) in dichloromethane (2 ml) at -78°C, a solution of boron trichloride in dichloromethane (1.29 ml, 1 M, 1.29 mmol) was slowly added along the wall of the flask so to keep the internal temperature below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml) followed by anhydrous ethanol (1 ml). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 3 ml), then dissolved in dimethyl sulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 µm 100 Å AXIA™ (30 mm × 75 mm) column with a gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at speed flow 50 ml/minute (0-1.0 minutes 5% A, 1.0-8.5 minutes linear gradient 5-100% A, 8.5-11.5 minutes 100% A, 11.5-12, 0 min linear gradient 95-5% A) to give the title compound as ammonium salt (0.0178 g, 0.045 mmol, 13.9% yield). ¹ H NMR (400 MHz, 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 (td, J =7.0, 4.2 Hz, 2H), 1.51 (k, J =7.0 Hz, 2H), 0.89-0.78 (m, 1H), 0.50-0.37 (m, 2H), 0.14-0.06 (m, 2H); MS (ESI ^- ) m/z 378 [MH] ^- .

Example 126: 5-[1-Fluoro-3-hydroxy-7-(4-methyl-1 H -imidazol-2-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trione (Compound 225)

Example 126A: 5-[3-(Benzyloxy)-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl]-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione

To a 100 ml flask was added the product of example 1G (2.50 g, 5.37 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (0.219 g, 0.269 mmol), 4.4 ,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.18 g, 8.60 mmol) and potassium acetate (1 .58 g, 16.1 mmol). The flask was stoppered, emptied and refilled with nitrogen. The empty/refill cycle was further repeated three times. Thereafter, 1,4-dioxane (27 ml) degassed by the above empty/refill process was added. Then the flask was heated to 80°C for 18 hours. The mixture was cooled to ambient temperature and filtered through diatomaceous earth with ethyl acetate. The filter cake was washed with ethyl acetate (2 × 100 ml). The filtrate was washed with 0.1 M hydrochloric acid (200 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with brine (3×100 ml), dried over sodium sulfate and concentrated under reduced pressure. The remaining solid was triturated with dichloromethane and collected by filtration. The collected material was washed with dichloromethane followed by t -butyl methyl ether and finally dried in vacuo to give the title compound (1.93 g, 3.77 mmol, 70% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.30 (s, 1H), 7.87 (d, J =8.3 Hz, 1H), 7.79 (dd, J = 8.1, 1.2 Hz, 1H), 7.53 (dd, J = 8.1, 1.7 Hz, 2H), 7.47 (s, 1H), 7.41-7.36 (m , 2H), 7.36-7.31(m, 1H), 5.29(s, 2H), 4.46(s, 2H), 1.33(s, 12H); MS (CIAD ⁺ ) m/z 530.4 [M+NH ₄ ] ⁺ .

Example 126B: 5-[3-(Benzyloxy)-1-fluoro-7-(4-methyl-1H-imidazol-2-yl)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione, hydrochloric acid

To a microwave tube was added the product of Example 126A (0.025 g, 0.049 mmol), 2-bromo-4-methyl- 1H -imidazole (0.016 g, 0.098 mmol), potassium carbonate (0.020 g, 0.15 mmol) and [ (1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2′-amino-1,1′-biphenyl)]palladium (II) methanesulfonate ( meCgPPh Pd G3, 3.23 mg, 4.88 µmol). The flask was sealed, emptied and refilled with nitrogen. The empty/refill cycle was further repeated three times. Thereafter, 1,4-dioxane (0.20 ml) and water (0.049 ml) were added, degassed by the empty/refill process described above. Then the tube was heated to 125°C for 5 hours. The tube was cooled to ambient temperature. After that was added acetonitrile (2 ml) and then 1 M hydrochloric acid (6 ml). The resulting mixture was stirred for 5 minutes and the precipitate was collected by filtration. The solid was washed with acetonitrile (2 ml) and ethyl acetate (2 ml), then dried to give the title compound (0.017 g, 0.034 mmol, 69% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 14.56 (br s, 2H), 8.68 (d, J =1.6 Hz, 1H), 8.11-8, 03 (m, 2H), 7.59-7.53 (m, 3H), 7.48 (s, 1H), 7.40-7.36 (m, 2H), 7.34-7.29 ( m, 1H), 5.32 (s, 2H), 4.20 (s, 2H), 2.37 (s, 3H); MS (CIAD ⁺ ) m/z 467.3 [M+H] ⁺ .

Example 126C: 5-[1-fluoro-3-hydroxy-7-(4-methyl-1H-imidazol-2-yl)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin- ^1,1 , 3-trione

A flask containing a suspension of the product of Example 126B (0.084 g, 0.17 mmol) and 1,2,3,4,5-pentamethylbenzene (0.074 g, 0.50 mmol) in dichloromethane (1.7 mL) was cooled to -78 °C with stirring under nitrogen atmosphere. Thereafter, trichloroborane (1.0 M in dichloromethane) (1.34 ml, 1.34 mmol) was slowly added along the wall of the flask. The resulting mixture was stirred at -78° C. for 10 minutes and then the dry ice/acetone bath was changed to an ice/water bath. After 10 minutes the mixture was re-cooled to -78°C and extinguished with ethyl acetate (2 ml) and then ethanol (2 ml). The mixture was then allowed to warm to ambient temperature and stirred for 15 minutes. The mixture was concentrated under reduced pressure and the residue was treated with ethanol (2×5 ml) and concentrated again under reduced pressure. Heptanes (6 ml) were then added, the flask was sonicated and the solid was collected by filtration. The solid was then washed with heptanes (2×6 ml), heptanes/ethyl acetate (1:1 v/v) (2×6 ml), dichloromethane (2×6 ml) and acetonitrile (2×6 ml) to give 5 -[1-fluoro-3-hydroxy-7-(4-methyl-1 H -imidazol-2-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, hydrochloric acid as a solid, along with a small amount of impurities. This solid was dissolved in methanol, loaded onto diatomaceous earth, concentrated under reduced pressure and purified by reverse phase chromatography (30 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 dry ice]) to give the title compound (0.012 g, 0.032 mmol, 19% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.44 (s, 1H), 8.59 (s, 1H), 7.97 (s, 2H), 7.47 (s, 1H), 7.16 (s, 1H), 4.13 (s, 2H), 2.36 (s, 3H); MS (CIAD ⁺ ) m/z 377.4 [M+H] ⁺ .

Example 127 5-[7-(azetidin-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 226)

Example 127A: 5-{7-bromo-1-fluoro-3-[(2-methoxyethoxy)methoxy]naphthalen-2-yl}-2-[(2-methoxyethoxy)methyl]-1 λ 6 ^, 2,5- thiadiazolidin-1,1,3-trione

To a suspension of 5 5-(7-bromo-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (example 128A, 1.41 g, 3, 76 mmol) in dichloromethane (14 mL) under nitrogen atmosphere was added Hunig's base ( N,N -diisopropyethylamine) (1.97 mL, 11.3 mmol) to give a homogeneous solution. Thereafter, 2-methoxyethoxymethyl chloride (0.804 ml, 7.89 mmol) was added slowly over 2 minutes and the reaction mixture was stirred at room temperature. After 30 minutes the mixture was diluted with dichloromethane (20 ml), extinguished with saturated aqueous NaHCO ₃ (10 ml) and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude solid was dissolved in ethyl acetate (50 ml), washed with water (3 x 30 ml) and brine (1 x 30 ml), dried over sodium sulfate, filtered and concentrated to give the title compound (1.76 g, 3 .19 mmol, 85% yield. MS (APCI ⁺ ) m/z 553 [M+H] ⁺ .

Example 127B: tert-butyl 3-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene -2-yl}azetidine-1-carboxylate

5-{7-bromo-1-fluoro-3-[(2-methoxyethoxy)methoxy]naphthalen-2-yl}-2-[(2-methoxyethoxy)methyl]-1λ ⁶ ,2,5 -thiadiazolidin-1,1,3-trione (example 127A, 120 mg, 0.218 mmol, 1.0 eq.) and Pd SPhos G4 (8.64 mg, 10.88 μmol, 0.05 eq.) in N, N -dimethylacetamide (2 ml). (1-( tert -Butoxycarbonyl)azetidin-3-yl)zinc (II) iodide (4.35 ml, 0.435 mmol, 2.0 eq., 0.11 M in tetrahydrofuran) was added. The tube was purged with N ₂ , stoppered and heated to 65° C. overnight. The reaction mixture was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 25% A, 0.5-8.0 min linear gradient 25 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-25% A, 9.1-10.0 minutes 25% A) to give the title compounds (65 mg, 55% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.87 (dd, J =8.6, 1.5 Hz, 1H), 7.85-7.81 (m, 1H), 7.57 (dd, J =8.5, 1.8 Hz, 1H), 7.37 (s, 1H), 5.36 (s, 2H), 4.33-4.30 (m, 2H) , 4.07 (s, 2H), 3.99 (tt, J = 8.5, 5.9 Hz, 1H), 3.91 (s, 2H), 3.83-3.77 (m, 2H ), 3.50-3.45 (m, 2H), 3.23 (s, 3H), 1.42 (s, 9H); MS (ESI ^- ) m/z 538.1 (MH) ⁺ .

Example 127C: 5-[7-(azetidin-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione

tert -butyl 3-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl }azetidine-1-carboxylate was dissolved in 4 M HCl in dioxane (1 ml) and stirred until complete consumption of the starting material. The reaction mixture was purified by reverse phase HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (7.8 mg, 18% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.90 (d, J =1.7 Hz, 1H), 7.77 (d, J =8.5 Hz, 1H), 7 .51 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (s, 1H), 4.31-4.25 (m, 2H), 4.15-4.11 (m , 3H); MS (ESI ⁺ ) m/z 352.2 (M+H) ⁺ .

Example 128: 5-[1-Fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione ( Compound 227)

Example 128A: 5-(7-bromo-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A dry 250 ml round bottom flask was filled with 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (2.5 g, 5.37 mmol, example 1G) and pentamethylbenzene (1.593 g, 10.75 mmol). The vessel was purged with dry nitrogen for 5 minutes and then filled with dichloromethane (50 ml). The mixture was cooled to -78°C. Thereafter, a 1 M solution of BCl ₃ (16.12 ml, 16.12 mmol) in dichloromethane was added dropwise over 15 minutes. After another 30 minutes, the reaction was quenched at -78°C with ethyl acetate (20 ml) followed by rapid addition of methanol (5.22 ml, 129 mmol) and then slowly warmed to room temperature over 20 minutes under nitrogen atmosphere. The volatiles were removed under reduced pressure to give a solid. The solid was suspended with ethyl acetate/heptanes (1:1, 20 ml), stirred for 5 minutes, then isolated by fritted filtration. The product was washed/suspended with more ethyl acetate/heptanes (1:1, 2 x 5 ml) followed by heptanes (2 x 5 ml) and dried to give the title compound (1.55 g, 4.13 mmol , 77% yield. 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); MS (CIAD ^- ) m/z 372.8 (MH) ^- .

Example 128B: 5-[1-Fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalen-2-yl]-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione

A microwave tube was filled with the compound from Example 128A (60 mg, 0.160 mmol), (4-methoxy-thiophen-2-yl)boronic acid (30.3 mg, 0.192 mmol) and K ₂ CO ₃ (66.3 mg, 0.480 mmol). A solution of dioxane (1 ml) in water (0.333 ml) was added. The mixture was sparged with N ₂ for 5 minutes before adding 1,1'-bis(di- tert -butylphosphino)ferrocene palladium dichloride (10.42 mg, 0.016 mmol). The mixture was then heated to 60° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, filtered and purified by preparative HPLC on Phenomenex® Luna® 10 µm C18 columns (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) with 0.1% trifluoroacetic acid at a flow rate of 50 ml/minute (0-1 min 10% A, 1-20 min linear gradient 10-100%) to give the title compound (28 mg, 0.069 mmol, 42 yield, 9%). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.60 (s, 1H), 8.02 (d, J =1.6 Hz, 1H), 7.84-7.71 ( m, 2H), 7.35 (d, J =1.7 Hz, 1H), 7.09 (s, 1H), 6.60 (d, J =1.6 Hz, 1H), 4.40 ( s, 2H), 3.77 (s, 3H); MS (APCI ⁺ ) m/z 308.8 (M+H) ⁺ .

Example 129: [8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetonitrile (Compound 228)

Example 129A: [6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]acetonitrile

A mixture of the compound from Example 1G (168 mg, 0.36 mmol), 1,1'-bis(di -tert -butylphosphino)ferrocene]palladium (II) dichloride (23.46 mg, 0.036 mmol), isoxazol-4-ylboronic acid (85 mg, 0.756 mmol) and cesium carbonate (328 mg, 1.008 mmol) in tetrahydrofuran (2.5 ml) and water (0.25 ml) were degassed and filled with nitrogen five times. The mixture was heated to 115°C for 4 hours, cooled to ambient temperature and diluted with dichloromethane (50 ml). The organic phase was washed with an aqueous solution of 0.1 N HCl (15 ml), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (12 g) and eluted with dichloromethane/methanol (0 to 10%) to give the title compound (85 mg, 0.20 mmol, 55.5% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.92 (s, 1H), 7.88 (brd, J =8 Hz, 1H), 7.54 (d, J = 8 Hz, 2H), 7.51 (dd, J =8.2 Hz, 1H), 7.35 (m, 4H), 5.27 (s, 2H), 4.22 (s, 2H), 4 .09 (s, 2H); MS (ESI ^- ) m/z 424 (MH) ^- .

Example 129B: [8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetonitrile

The title compound was prepared using the procedures described in Example 137B, replacing the compound from Example 129A with the compound from Example 137A. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.62 (br s, 1H), 7.89 (s, 1H), 7.79 (br d, J =8, Hz 1H), 7.48 (dd, J = 8.2 Hz, 1H), 7.15 (s, 1H), 4.42 (s, 2H), 4.19 (s, 2H); MS (ESI ^- ) m/z 334 (MH) ^- .

Example 130 5-[1-Fluoro-3-hydroxy-7-(methoxymethyl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 229)

NiCl ₂ adduct of dimethoxyethane (3.4 mg, 0.015 mmol, 0.12 equiv.) and 4,4'-di -tert -butyl-2,2'-dipyridyl (4.15 mg, 0.015 mmol , 0.12 eq.) in N,N -dimethylacetamide (1.0 ml). Example 1G (60 mg, 0.13 mmol, 1.0 eq), potassium trifluoro(methoxymethyl)borate (58 mg, 0.39 mmol, 3.0 eq), cesium carbonate (105 mg, 0 ,32 mmol, 2.5 eq.) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium (1+), 2-(2-pyridyl)pyridine, hexafluorophosphate (4.3 mg, 0.004 mmol, 0.03 eq.), followed by dioxane (1.0 ml). The reaction was irradiated overnight using a 450 nm diode photoreactor.

The reaction was filtered and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give 5-[ 3-(benzyloxy)-1-fluoro-7-(methoxymethyl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (52.4 mg, 94% yield).

5-[3-(benzyloxy)-1-fluoro-7-(methoxymethyl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (52.4 mg, 0.122 mmol) and tetrahydrofuran (2 ml) was added in 5% Pd/C (wet JM#9) (27 mg, 0.118 mmol) in a 20 ml Barnstead Hast C reactor and stirred for 41.6 hours at 70 psi. inch of hydrogen and 25°C. Methanol and 5% Pd/C (wet JM#9) (27.8 mg, 0.122 mmol) were added and the reaction mixture was hydrogenated for 3.5 hours. The reaction mixture was filtered and concentrated under a stream of nitrogen. The residue was dissolved in dimethyl sulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give the title compounds (9 mg, 22% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.84 (s, 1H), 7.76 (dd, J =8.6, 1.5 Hz, 1H), 7.47 ( dd, J = 8.6, 1.6 Hz, 1H), 7.12 (s, 1H), 4.57 (s, 2H), 4.18 (s, 2H), 3.34 (s, 3H ).

Example 131: 5-{1-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione (Compound 230)

Example 131A: 5-{3-(Benzyloxy)-1-fluoro-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione

To a solution of the product of Example 1H (140 mg, 0.348 mmol) in N,N -dimethylformamide (2 mL) was added (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (196 mg, 0.765 mmol) and cesium carbonate (249 mg, 0.765 mmol). The reaction mixture was heated to 40° C. overnight. The mixture was then cooled to ambient temperature and filtered. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (120 mg, 0.247 mmol, 71% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.77 (dd, J =8.9, 1.4 Hz, 1H), 7.59-7.50 (m, 2H), 7.45-7.34 (m, 2H), 7.31 (k, J = 2.6 Hz, 3H), 7.24 (dd, J = 9.0, 2.6 Hz, 1H), 5 .22 (s, 2H), 4.56 (d, J = 5.8 Hz, 2H), 4.33 (d, J = 5.8 Hz, 2H), 4.19 (s, 2H), 4 .09 (s, 2H), 1.91 (s, 1H), 1.41 (s, 3H); MS (CIAD ^- ) m/z 485 [MH] ^- .

Example 131B: 5-{1-Fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione

A 250 ml round bottom flask was filled with nitrogen followed by the addition of 5% Pd/C (100 mg, 0.940 mmol) and tetrahydrofuran (10 ml). Then a solution of the product of example 131A (40 mg, 0.083 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. The filtrate was concentrated under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (12 mg, 0.030 mmol, 15% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.73 (d, J =9.0 Hz, 1H), 7.28 (d, J =2.6 Hz, 1H), 7 .23 (dd, J =9.0, 2.5 Hz, 1H), 7.08 (s, 1H), 4.54 (d, J =5.8 Hz, 2H), 4.48 (s, 3H), 4.33 (d, J =5.8 Hz, 2H), 4.17 (s, 2H), 1.40 (s, 3H); MS (CIAD ^- ) m/z 395 [MH] ^- .

Example 132A and Example 132B: 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl} -1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (product A, Compound 231A) and 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1 H -pyrrol-3-yl ]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Product B, Compound 231B)

To a solution of the compound from Example 14 (20 mg, 0.043 mmol) in N,N -dimethylformamide (0.5 ml) was added N -bromosuccinimide (7.61 mg, 0.043 mmol) and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was combined with another similar reaction with 10 mg of the compound from example 14 and 3.8 mg of N -bromosuccinimide and purified by preparative HPLC on a 10 μl Phenomenex® Luna®, C18 column (30 mm × 250 mm), eluted with an acetonitrile gradient (A) with 0.1% trifluoroacetic acid and water (B) with 0.1% trifluoroacetic acid at a flow rate of 50 ml/minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) c obtaining the title compounds 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}- 1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (17 mg, 0.031 mmol, 48.5% yield) (product A) and 5-{4-bromo-7-[1-(cyclopropanesulfonyl)- 1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (5 mg, 9.18 µmol, yield 14 %) (product B).

Product A: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.25 (s, 1H), 8.08-8.01 (m, 1H), 7.98 (dd, J = 9.0, 1.8 Hz, 1H), 7.85 (d, J =1.7 Hz, 1H), 6.65-6.59 (m, 1H), 4.71-4.64 (m , 2H), 4.38 (k, J = 3.7, 3.2 Hz, 2H), 4.25 (s, 2H), 2.87-2.79 (m, 1H), 1.05 ( m, 2H), 1.03-0.93 (m, 2H); MS (APCI ⁺ ) m/z 545.8 (M+H) ⁺ .

Product B: ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.97 (s, 1H), 8.21 (d, J =1.6 Hz, 1H), 8.09-8 .01 (m, 2H), 7.95 (t, J = 2.0 Hz, 1H), 7.36 (dd, J = 3.3, 2.2 Hz, 1H), 7.05 (dd, J = 3.3, 1.7 Hz, 1H), 4.18 (s, 2H), 1.31 (m, 2H), 1.21-1.13 (m, 2H); MS (CIAD ^- ) m/z 543.7 (MH) ^- .

Example 133: 5-{1-Fluoro-3-hydroxy-7-[(3 S )-pyrrolidin-3-yl]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione (Compound 232)

Example 133A: tert-butyl (3S)-3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene- 2-yl]pyrrolidine-1-carboxylate

To a solution of the compound from Example 14A (3 g, 4.61 mmol) in methanol (50 ml) and tetrahydrofuran (50 ml) was added tris(triphenylphosphine)rhodium(I) chloride (0.426 g, 0.461 mmol) at 20°C, and stirred the mixture for 24 hours at 25°C in an atmosphere of H ₂ (50 psi). One additional 3 g tube was prepared and reacted as described above. All mixtures were combined and concentrated under reduced pressure. The residue was purified by reverse phase HPLC [Agela 20-35 μm 100 Å, 330 g flash column, flow rate 100 ml/min, 10-100% acetonitrile gradient in water] to give the crude title compound (4 g) . The crude title compound was separated by chiral SLC (Waters prep-SFC 80Q; column: CHIRALPAK® IC-H, 250×30 mm id, 5 µm; mobile phase: A for CO ₂ and B for ethanol:acetonitrile =4:1 (0.1% ammonium hydroxide); gradient: B%=50%; flow rate: 70 g/minute; column temperature: 40° C.; system back pressure: 100 bar) to give the title compound tert - butyl (3 S )-3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidine -1-carboxylate (680 mg, 12.62% yield, peak 1, first eluting compound, arbitrary stereochemistry, product A) and tert -butyl ( 3R )-3-[6-(benzyloxy)-8-fluoro- 7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidine-1-carboxylate (480 mg, 8.91% yield, peak 2, second eluted compound, stereochemistry is arbitrary, product B). Product A: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.43 (brd, J= 3.55 Hz, 10H), 2.03-2.11 (m, 1H) , 2.19-2.32 (m, 1H), 3.20-3.27 (m, 2H), 3.43-3.59 (m, 2H), 3.77 (dd, J= 10, 27, 7.70 Hz, 1H), 4.08 (s, 2H), 5.26 (s, 2H), 6.93-7.24 (m, 4H), 7.27-7.42 (m , 4H), 7.48-7.60 (m, 3H), 7.75-7.83 (m, 2H); Product B: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.42 (d, J= 5.14 Hz, 9H), 2.05 (br d, J= 10.03 Hz , 1H), 2.26 (br s, 1H), 3.21-3.31 (m, 2H), 3.44-3.59 (m, 2H), 3.76 (dd, J= 10 .27, 7.70 Hz, 1H), 4.07 (s, 2H), 5.25 (s, 2H), 6.92-7.24 (m, 1H), 7.27-7.40 ( m, 4H), 7.47-7.60 (m, 3H), 7.74-7.84 (m, 2H).

Example 133B: tert-butyl (3S)-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2- yl]pyrrolidine-1-carboxylate

To a mixture of 10% Pd/C (50 mg, 0.470 mmol) in methanol (10 ml) was added the compounds from example 133A, product A (50 mg, 0.090 mmol) at 25°C and the mixture was stirred for 2 hours at 25°C in an H ₂ atmosphere (15 psi). The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC on a 5 μm Xtimate™ C18 150×25 mm column, eluted with 20-100% acetonitrile in H ₂ O, containing 10 mM NH ₄ HCO ₃ for 20 minutes at a flow rate of 25 ml/minute to obtain the title compound (25 mg, 56.7% yield). MS (IER ^- ) m / z 464 (MH) ^-

Example 133C: 5-{1-Fluoro-3-hydroxy-7-[(3S)-pyrrolidin-3-yl]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trion

To a solution of the compound from example 133B (25 mg, 0.051 mmol) in ethyl acetate (1 ml) was added HCl/ethyl acetate (5 ml, 165 mmol) at 25°C, and the mixture was stirred for 2 hours at 25°C. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (Xtimate™ C18 150×25 mm, 5 µm column, eluting with acetonitrile in H ₂ O containing 10 mM NH ₄ HCO ₃ [0.0-10 min, 10-40% B; 10-10 .1 minute, 40% B; 10.1-10.2 minutes; 40-100% B; 10.2-16.2 minutes, 100% B; 16.2-16.3 minutes, 100-10% B ; 16.3-17.5 minutes, 10% B, minutes] at a flow rate of 25 ml/minute, monitoring at 220 and 254 nm) to give the title compound (10 mg, 53.3% yield). ¹ HNMR (400 MHz, DMSO- d ₆ ) δ ppm 1.93-2.10 (m, 1H), 2.35-2.42 (m, 1H), 3.11-3.24 ( m, 2H), 3.45-3.50 (m, 1H), 3.54-3.73 (m, 2H), 4.09 (s, 2H), 7.06 (s, 1H), 7 .46 (dd, J = 8.68, 1.59 Hz, 1H), 7.75 (d, J = 8.44 Hz, 1H), 7.80 (s, 1H), 8.58-9, 34 (m, 1H); MS (ESI ^- ) m / z 364 (MH) ^- .

Example 134: 5-{1-Fluoro-3-hydroxy-7-[(3 R )-pyrrolidin-3-yl]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione (Compound 233)

The title compound was prepared from the compound of Example 133A, Product B using the methods described for Example 133B and Example 133C. ¹ HNMR (400 MHz, DMSO- d ₆ ) δ ppm 2.03 (dc, J = 12.73, 9.33 Hz, 1H), 2.35-2.42 (m, 1H), 3 .11-3.27 (m, 1H), 3.43-3.50 (m, 1H), 3.54-3.74 (m, 2H), 4.09 (s, 2H), 7.06 (s, 1H), 7.46 (dd, J =8.56, 1.59 Hz, 1H), 7.75 (d, J =8.56 Hz, 1H), 7.80 (s, 1H) , 8.34-9.87 (m, 2H); MS (ESI ^- ) m / z 364 (MH) ^- .

Example 135 5-(8-Chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 234)

Example 135A: benzyl 3-(benzyloxy)-8-chloro-7-methoxynaphthalene-2-carboxylate

To a solution of the compound from Example 25A (3.3 g, 7.87 mmol) in dichloromethane (30 mL) were added in order zirconium(IV) chloride (0.275 g, 1.180 mmol) and 1-chloropyrrolidine-2,5-dione (1.051 g, 7.87 mmol) at 20°C. The mixture was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether:ethyl acetate=20:1) to give the title compound (2.53 g, 5.73 mmol, 72.8% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.41 (s, 1H), 7.91 (d, J =9.04 Hz, 1H), 7.70 (s, 1H) , 7.65 (d, J = 9.26 Hz, 1H), 7.45-7.52 (m, 2H), 7.31-7.44 (m, 8H), 5.37 (s, 2H ), 5.27 (s, 2H), 3.98 (s, 3H); MS (ESI ⁺ ) m / z 433 (M+H) ⁺ .

Example 135B: 3-(benzyloxy)-8-chloro-7-methoxynaphthalene-2-carboxylic acid

To a solution of the compound from Example 135A (2.53 g, 5.73 mmol) in methanol (20 ml), tetrahydrofuran (20 ml) and water (10 ml) was added a solution of sodium hydroxide (0.229 g, 5.73 mmol) in water (2 ml) at 20°C. The mixture was refluxed at 60°C for 3 hours. The mixture was extracted with ethyl acetate (30 ml). The aqueous phase was adjusted to pH=3 with aqueous hydrochloric acid (1M). A solid precipitated out. The solid was then collected by filtration and the solid was dried under high vacuum to give the title compound (1.67 g, 4.77 mmol, 83% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.31-8.35 (m, 1H), 7.86-7.92 (m, 1H), 7.59-7.66 (m, 2H), 7.52-7.57 (m, 2H), 7.38-7.44 (m, 2H), 7.30-7.36 (m, 1H), 5.28 (s , 2H), 3.98 (s, 3H); MS (ESI ⁺ ) m / z 343 (M+H) ⁺ .

Example 135C: tert-butyl [3-(benzyloxy)-8-chloro-7-methoxynaphthalen-2-yl]carbamate

To a solution of the compound from Example 135B (1.45 g, 4.15 mmol) in toluene (15 mL) were added in order triethylamine (1.733 mL, 12.44 mmol), tert -butanol (15 mL), and diphenylphosphoryl azide (2.282 g, 8.29 mmol) at 20°C. The mixture was stirred at 110°C for 3 hours under nitrogen. One additional 100 mg tube was prepared and reacted as described above. The mixtures were combined and concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (2.2 g, 4.643 mmol, 97.2% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.50-8.59 (m, 1H), 8.08 (s, 1H), 7.72-7.77 (m, 1H ), 7.53-7.60 (m, 2H), 7.47-7.53 (m, 1H), 7.34-7.45 (m, 4H), 5.29 (s, 2H), 3.94 (s, 3H), 1.49 (s, 9H); MS (ESI ⁺ ) m / z 314, 358, 414 (M-99, M-55, M+H) ⁺ .

Example 135D: 3-(benzyloxy)-8-chloro-7-methoxynaphthalene-2-amine

Trifluoroacetic acid (5 ml, 64.9 mmol) was added dropwise to a solution of the compound from Example 135C (996 mg, 2.222 mmol) in dichloromethane (15 ml) at 0°C. The mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was diluted with water (20 ml) and saturated aqueous sodium bicarbonate was added to adjust the pH to 9. The mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (996 mg, 2.22 mmol, 92% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.53-7.60 (m, 4H), 7.39-7.44 (m, 3H), 7.14 (s, 1H ), .06-7.10 (m, 1H), 5.50 (s, 2H), 5.23 (s, 2H), 3.88 (s, 3H); MS (ESI ⁺ ) m / z 313 (M+H) ⁺ .

Example 135E: methyl {[3-(benzyloxy)-8-chloro-7-methoxynaphthalen-2-yl]amino}acetate

Potassium carbonate (0.969 g, 7.01 mmol) was added to a solution of the compound from Example 135D (1.1 g, 3.51 mmol) in N,N -dimethylformamide (10 mL) at 20°C and the mixture was stirred for 5 minutes . Bromoacetate (0.485 ml, 5.26 mmol) was then added. The mixture was stirred at 70°C for 3 hours. The solution was diluted with water (50 ml) and the resulting mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (3×25 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [5 μm Phenomenex® Luna® C18 100×30 mm column, flow rate 25 ml/min, 50-80% acetonitrile gradient in water (10 mM trifluoroacetic acid solution)] and lyophilized to give the title compound (610 mg, 1.265 mmol, 36.1% yield). MS (ESI ⁺ ) m / z 386 (M+H) ⁺ .

Example 135F: methyl {[3-(benzyloxy)-8-chloro-1-fluoro-7-methoxynaphthalen-2-yl]amino}acetate

To a solution of the compound from Example 135E (500 mg, 1.037 mmol) in N,N -dimethylformamide (6 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) ( Selectfluor®, 441 mg, 1.244 mmol) at 0° C. and the mixture was stirred for 5 minutes. The reaction was then quenched with saturated aqueous sodium thiosulfate (20 ml). The mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (70 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using a flash column (petroleum ether/ethyl acetate=5:1) to give the title compound (300 mg, 0.706 mmol, 68.1% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.68 (dd, J =8.93, 1.43 Hz, 1 H), 7.54 (d, J =7.28 Hz , 2 H), 7.39-7.46 (m, 2 H), 7.33-7.39 (m, 1 H), 7.21-7.29 (m, 2 H), 5.54 -5.61(m, 1H), 5.25(s, 2H), 4.20(dd, J =6.50, 3.64Hz, 2H), 3.90(s, 3H ), 3.61 (s, 3H); MS (ESI ⁺ ) m / z 404 (M+H) ⁺ .

Example 135G: methyl {[3-(benzyloxy)-8-chloro-1-fluoro-7-methoxynaphthalen-2-yl][(t-butoxycarbonyl)sulfamoyl]amino}acetate

To a solution of sulfurisocyanatide chloride (200 mg, 1.411 mmol) in dichloromethane (6 ml) was added dropwise a solution of tert -butanol (0.135 ml, 1.411 mmol) in dichloromethane (6 ml) at 20°C and the mixture was stirred for 30 minutes at 20 °C. The mixture was then added dropwise to a solution of the compound from Example 135F (300 mg, 0.706 mmol) and triethylamine (0.393 ml, 2.82 mmol) in dichloromethane (6 ml) at 20°C, and the resulting mixture was stirred for 60 minutes at 20°C. The mixture was concentrated under reduced pressure to give the title compound (880 mg, crude) which was used in the next step without further purification. MS (ESI ⁺ ) m / z 605(M+Na) ⁺ .

Example 135H: methyl {[3-(benzyloxy)-8-chloro-1-fluoro-7-methoxynaphthalen-2-yl](sulfamoyl)amino}acetate

Trifluoroacetic acid (3 ml, 38.9 mmol) was added dropwise to a solution of the compound from Example 135G (880 mg, crude) in dichloromethane (9 ml) at 0°C, and the mixture was stirred for 2 hours at 20°C. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 ml) and adjusted to pH=9 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (390 mg, 0.646 mmol, 89% yield). MS (ESI ⁺ ) m / z 505(M+Na) ⁺ .

Example 135I: 5-[3-(Benzyloxy)-8-chloro-1-fluoro-7-methoxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from example 135H (390 mg, 0.646 mmol) in tetrahydrofuran (3 ml) was added sodium methoxide (175 mg, 0.969 mmol, 30% in methanol) at 20° C. under nitrogen and the mixture was stirred for 2 hours at 20 °C. The pH of the mixture was adjusted to pH=4 with aqueous hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (200 mg, 0.399 mmol, 61.8% yield), which was used for the next step without further purification. MS (ESI ^- ) m / z 449(MH) ^- .

Example 135J: 5-(8-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a solution of the compound from example 135I (120 mg, 0.240 mmol) in dichloromethane (3 ml) was added boron trichloride (1.198 ml, 1.198 mmol) at -65°C and the mixture was stirred for 1 hour at -65°C. One additional 10 mg tube was prepared and reacted as described above. The reaction mixture was quenched by adding methanol (3 ml). The reaction mixtures were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC [Xtimate™ C18, 150×25 mm, 5 µm column, flow rate 25 ml/min, 15-40% acetonitrile gradient in water (10 mM ammonium bicarbonate solution)] and lyophilized to give the title compound (17 mg, 0.043 mmol, 16.5% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.73-7.78 (m, 1 H), 7.48 (d, J =9.21 Hz, 1 H), 7, 09 (s, 2H), 4.06 (s, 2H), 3.94 (s, 3H); ¹⁹ F NMR (377 MHz, DMSO- d ₆ ) δ ppm -118.23 (s, 1F); MS (ESI ^- ) m / z 359 (MH) ^- .

Example 136: 5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin- ^1,1,3 -trione ( Compound 235)

In a 20 ml tube, the compound from example 1H (511 mg, 1.270 mmol, 1.0 eq.), 3-(bromomethyl)-1,1-difluorocyclobutane (470 mg, 2.54 mmol, 2.0 eq.) and cesium carbonate (1241 mg, 3.81 mmol, 3.0 eq.) in N,N -dimethylformamide (5 mL). The reaction mixture was heated overnight at 50°C. The material was diluted with aqueous 1M HCl and extracted with ethyl acetate. The organic fraction was washed with NH ₄ Cl (2×) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane) to give 5-{3-(benzyloxy)-7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoronaphthalen-2-yl}-1λ ^6,2,5 -thiadiazolidin-1,1,3-trione (409 mg, 64% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) 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).

5-{3-(benzyloxy)-7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (406 mg , 0.802 mmol) in tetrahydrofuran (4.0 mL) was added in 5% Pd/C (wet JM#9) (108 mg, 0.451 mmol) to a 20 mL RS10 Hast C reactor. The reactor was purged with argon. The mixture was stirred at 1200 rpm at 65 psi. inch of hydrogen at 25°C. After 16.3 hours the reactor was vented. The mixture was filtered through a filter funnel with a polyethylene filter separator packed with diatomaceous earth as a solution of tetrahydrofuran (4.0 ml). The catalyst was washed successively with methanol (2×) and again with tetrahydrofuran. The combined filtrate and washing material was concentrated by rotary evaporation to obtain a film. After placing the film in a laboratory vacuum for 10 minutes, foam was formed. The material was triturated with dichloromethane/heptanes to give the title compound as a solid (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 137 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 236)

Example 137A: 5-[3-(benzyloxy)-7-cyclopropyl-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Mixture of the compound from Example 1G (140 mg, 0.3 mmol), 1,1'-bis(di -tert -butylphosphino)ferrocene]palladium (II) dichloride (29.3 mg, 0.045 mmol), 2-cyclopropyl-4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane (136 mg, 0.810 mmol) and cesium carbonate (293 mg, 0.900 mmol) in tetrahydrofuran (2.5 ml) and water (0.23 ml) were degassed and filled with nitrogen five times, then the mixture was heated to 115°C for 3 hours. The mixture was cooled to ambient temperature and diluted with dichloromethane (50 ml). The organic phase was washed with an aqueous solution of 0.1 N HCl (15 ml), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (40 g) and eluted with dichloromethane/methanol (0 to 10%) to give the title compound (85 mg, 0.199 mmol, 66.4% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.72 (brd, J =8 Hz, 1H), 7.61 (d, J =2 Hz, 1H), 7.56 (m, 2H), 7.35 (m, 3H), 7.26 (m, 2H), 5.23 (s, 2H), 4.09 (s, 2H), 2.11 (m, 1H) , 1.01 (m, 2H), 0.79 (m, 2H); MS (ESI ^- ) m/z 425 (MH) ^- .

Example 137B: 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Trichloroborane (0.985 ml , 0.985 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 20 minutes and then quenched with ethanol (3 ml). The mixture was stirred at 0°C for 5 minutes and then concentrated. The resulting solid was washed with heptane (4 x 2 ml) and dichloromethane (4 x 2 ml) and concentrated to give the title compound (46 mg, 0.137 mmol, 83% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.41 (br s, 1H), 7.67 (br d, J =8 Hz, 1H), 7.58 (d, J =2Hz, 1H), 7.23(dd, J =8.2Hz, 1H), 7.07(s, 1H), 4.44(s, 2H), 2.09(m, 1H) , 1.00 (m, 2H), 0.77 (m, 2H); MS (ESI ^- ) m/z 335 (MH) ^- .

Example 138: 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H- pyrrol -3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione (Compound 237)

Example 138A: 3 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl) - 2.5 - dihydro - 1H - pyrrole

Into a solution of tert -butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1 H -pyrrole-1-carboxylate (250 mg, 0.847 mmol) in methylene chloride (2 ml) trifluoroacetic acid (2 ml) was added. The reaction mixture was stirred at ambient temperature for 2 hours. The volatiles were removed under reduced pressure and the residue was used in the next step without further purification.

Example 138B: cyclopropyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrol-1-yl) methanone

To a solution of crude 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro- 1H -pyrrole (250 mg, 1.282 mmol) and cyclopropanecarbonyl chloride ( 147 mg, 1.410 mmol) in tetrahydrofuran (2 ml) was added triethylamine (0.876 ml, 6.41 mmol). The mixture was stirred at room temperature for 14 hours. The mixture was diluted with water and then extracted with ethyl acetate. The combined organic fractions were washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used for the next step without further purification. MS (APCI ⁺ ) m/z 264 [M+H] ⁺ .

Example 138C: 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3 - hydroxynaphthalen-2-yl}-1 λ ^6.2.5 -thiadiazolidin-1,1,3-trione

A microwave tube was filled with the product of Example 128A (250 mg, 0.666 mmol), crude cyclopropyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro -1H- pyrrol-1-yl)methanone (Example 138B, 263 mg, 1 mmol), potassium carbonate (276 mg, 1.999 mmol) and 1,1'-bis(di- tert -butylphosphino)ferrocene palladium dichloride (8 .69 mg, 0.013 mmol). 1,4-dioxane (2 ml) and water (1 ml) were added successively. The reaction mixture was purged with N ₂ for 5 minutes, after which it was heated to 70°C. After 1.5 hours, the reaction mixture was cooled to ambient temperature, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [column Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ (250 mm × 25 mm), 30 -100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (30 mg, 0.070 mmol, 11% yield in three stage). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.99 (s, 1H), 7.78-7.63 (m, 3H), 7.15 (s, 1H, NH ₃ ) , 7.03 (s, 1H, NH ₃ ), 7.02 (s, 1H), 6.90 (s, 1H, NH ₃ ), 6.51 (dt, J =9.6, 2.0 Hz , 1H), 4.89 (td, J =3.8, 1.8 Hz, 1H), 4.60 (n, J =2.3 Hz, 1H), 4.51 (d, J =3, 0Hz, 1H), 4.23(k, J =3.3Hz, 1H), 4.09(s, 2H), 1.96(r, J =5.9, 5.4Hz, 1H) , 0.79-0.67 (m, 4H); MS (CIAD ^- ) m/z 430 [MH] ^- .

Example 139 5-(4-Chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 238)

To a solution of 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (30 mg, 0.092 mmol, Example 25 ) in N , N -dimethylformamide () (0.5 ml) was added N -chlorosuccinimide (12.28 mg, 0.092 mmol), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was purified on a Phenomenex® Luna® 10 µm preparative HPLC column, C18 (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) with 0.1% trifluoroacetic acid at a flow rate of 50 ml/minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) to give the title compound (12 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.16 (s, 1H), 7.99 (dd, J =9.2, 1.4 Hz, 1H), 7.38 ( dd, J = 9.2, 2.6 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 4.39 (s, 2H), 3.90 (s, 3H); MS (CIAD ^- ) m/z 358.7 (MH) ^- .

Example 140 5-{7-[( E )-2-cyclopropylethenyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 239)

To a solution of the product of example 128A (0.134 g, 0.36 mmol) was added dioxane:water (3:1, 4 ml), and after - ( E )-2-(2-cyclopropylvinyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.139 g, 0.714 mmol) and potassium carbonate (0.166 g, 1.199 mmol). This suspension was purged with N ₂ for 10 minutes and then 1,1'-bis(di- tert -butylphosphino)ferrocene palladium dichloride (0.00261 g, 0.004 mmol) was added. Blowing was continued for 5 minutes, and then the biphasic suspension was heated at 80°C for 12 hours. The mixture was allowed to cool to ambient temperature, and the volatiles were removed under reduced pressure. The resulting residue was purified on SiO ₂ (0-25% methanol in ethyl acetate) to give the title compound (0.048 g, 0.132 mmol, 37% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.76 (s, 1H), 7.69-7.62 (m, 2H), 7.58 (dd, J =8.7 , 1.7 Hz, 1H), 7.03 (d, J =1.2 Hz, 1H), 6.62 (d, J =15.8 Hz, 1H), 5.95 (dd, J =15 .8, 9.1 Hz, 1H), 4.10 (s, 2H), 1.66-1.56 (m, 1H), 0.86-0.76 (m, 2H), 0.58- 0.52 (m, 2H); MS (CIAD ^- ) m/z 361 [MH] ^- .

Example 141 5-{1-Fluoro-3-hydroxy-7-[(1 E )-4-methylpent-1-en-1-yl]naphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine -1,1,3-trione (Compound 240)

To a solution of the product of Example 128A (0.15 g, 0.4 mmol) was added dioxane:water (3:1, 4 mL, 0.1 M) followed by ( E )-(4-methylpent-1-ene- 1-yl)boronic acid (0.102 g, 0.8 mmol) and potassium carbonate (0.166 g, 1.199 mmol). This suspension was purged with N ₂ for 10 minutes and then 1,1'-bis(di- tert -butylphosphino)ferrocene palladium dichloride (0.00261 g, 0.004 mmol) was added. Blowing was continued for 5 minutes, and then the biphasic suspension was heated at 80°C for 12 hours. The mixture was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure to give the crude title compound, which was purified by reverse phase HPLC (Phenomenex® C8(2) Luna® 5 μm AXIA™ 150 x 30 mm column, 3-100% gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) over 17 minutes at a flow rate of 50 ml/minute to give the title compound (0.0783 g, 0.207 mmol, 52% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.68 (s, 1H), 7.62 (d, J =2.1 Hz, 2H), 7.00 (s, 1H) , 6.52 (d, J = 15.8 Hz, 1H), 6.41-6.26 (m, 1H), 4.05 (s, 2H), 2.08 (t, J = 6.9 Hz, 2H), 1.70 (dc, J = 13.3, 6.7 Hz, 1H), 0.90 (d, J = 6.6 Hz, 6H), MS (CIAD ^- ) m/z 377 [MH] ^- .

Example 142 5-{1-Fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione (Compound 241)

Example 142A: 5-{3-(Benzyloxy)-1-fluoro-7-[(trimethylsilyl)ethynyl]naphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3-trione

Mixture of the compound from Example 1G (186 mg, 0.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (25.3 mg, 0.036 mmol), copper(I) iodide (11.43 mg, 0.060 mmol) and ethenyltrimethylsilane (130 mg, 1.320 mmol) in triethylamine (0.7 g) and tetrahydrofuran (3.5 ml) were heated to 125 ° C for 60 minutes. The mixture was diluted with ethyl acetate (70 ml). The organic phase was washed with brine (3 ×15 ml), dried over sodium sulfate, filtered and concentrated to give the title compound (190 mg, 0.414 mmol, 98% yield). MS (ESI ^- ) m/z 481 (MH) ^- .

Example 142B: 5-[3-(Benzyloxy)-7-ethynyl-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Potassium carbonate (193 mg, 1.400 mmol) was added to the compound from Example 142A (190 mg, 0.4 mmol) in methanol (2.5 ml). The mixture was stirred at 25°C for 1 hour. The mixture was diluted with dichloromethane (5 ml) and filtered. The filtrate was concentrated. The resulting residue was purified by flash column chromatography on silica gel (40 g), eluted with ethyl acetate/methanol (0 to 10%) to give the title compound (110 mg, 0.268 mmol, 67% yield). MS (ESI ^- ) m/z 409 (MH) ^- .

Example 142C: 5-{1-Fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione

Trichloroborane (0.975 ml, 0.975 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 30 minutes and then at 0°C for 30 minutes. The mixture was quenched with ethanol (2 ml), stirred at 0°C for 5 minutes and then concentrated. The resulting residue was purified by flash column chromatography on silica gel (40 g), eluted with 0-100% ethyl acetate/heptane to give the title compound (67 mg, 0.143 mmol, 58.7% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.54 (br s, 1H), 7.76 (s, 2H), 7.37 (s, 1H), 7.09 ( s, 1H), 6.18 (s, 1H), 5.05 (s, 1H), 4.39 (s, 2H), 2.24 (s, 3H), 2.19 (s, 6H), 2.02 (s, 6H); MS (ESI ^- ) m/z 469 (M+H) ⁺ .

Example 143: 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione (Compound 242)

Example 143A: 5-[3-(Benzyloxy)-7-(2,5-dihydro-1H-pyrrol-3-yl)-1-fluoronaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione

Trifluoroacetic acid (2 ml) was added to a solution of the product from example 123A (800 mg, 1.44 mmol) in dichloromethane (5 ml). The mixture was stirred at ambient temperature for 30 minutes. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (474 mg, 1.05 mmol, 73% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.86 (d, J =3.7 Hz, 2H), 7.60-7.48 (m, 2H), 7.46- 7.27 (m, 5H), 6.60 (t, J =2.2 Hz, 1H), 5.28 (s, 2H), 4.50 (k, J =2.3 Hz, 2H), 4.19 (dt, J =5.0, 2.5 Hz, 2H), 4.10 (s, 2H); MS (CIAD ^- ) m/z 452 [MH] ^- .

Example 143B: 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ^6.2.5 -thiadiazolidin-1,1,3-trione

A 20 ml microwave tube was filled with the product from Example 143A (200 mg, 0.441 mmol) and N,N -dimethylformamide. Thereafter, cyclopropanecarbaldehyde (93 mg, 1.323 mmol) and acetic acid (0.126 ml, 2.205 mmol) were added and the mixture was stirred for 5 minutes at ambient temperature. Sodium cyanoborohydride (166 mg, 2.65 mmol) was then added. The mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was further extracted with ethyl acetate (2×3 ml) and the combined organic layers were washed with saturated aqueous ammonium chloride (5 ml) and dried over sodium sulfate. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give 5-{3-(benzyloxy)-7-[1-( cyclopropylmethyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (70 mg, 0.138 mmol , yield 31%). MS (CIAD ^- ) m/z 506 [MH] ^- .

A 50 ml round bottom flask was filled with 5-{3-(benzyloxy)-7-[1-(cyclopropylmethyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (68 mg, 0.134 mmol), 1,2,3,4,5-pentamethylbenzene (59.6 mg, 0.402 mmol) and methylene chloride (3 ml). The mixture was purged with nitrogen for 5 minutes. The heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.670 ml, 0.670 mmol) in dichloromethane was added dropwise over 5 minutes. The reaction was stirred at -78°C for 30 minutes. Ethyl acetate (1 ml) and methanol (0.2 ml) were added and the reaction was heated to ambient temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (22 mg, 0.053 mmol, 39% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.05 (s, 1H), 7.79 (d, J =3.6 Hz, 3H), 7.10 (d, J = 1.3 Hz, 1H), 6.58 (t, J =2.1 Hz, 1H), 4.63 (s, 2H), 4.30 (s, 2H), 4.10 (s, 2H) , 3.26-3.19 (m, 2H), 1.21-1.14 (m, 1H), 0.71-0.60 (m, 2H), 0.48-0.40 (m, 2H); MS (CIAD ^- ) 416 m/z [MH] ^- .

Example 144 5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 243)

To a solution of 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (20 mg, 0.061 mmol, example 25) in N , N -dimethylformamide (0.5 ml) was added N -bromosuccinimide (10.91 mg, 0.061 mmol) and the mixture was stirred at ambient temperature for 1 hour. The mixture was purified by preparative HPLC on a Phenomenex® Luna® 10 µm, C18 (30 mm × 250 mm) column, eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) with 0.1% trifluoroacetic acid at a flow rate of 50 ml/minute (0-1 min 10% A, 1-20 min linear gradient 10-100%) to give the title compound (22 mg, 89% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.97 (s, 1H), 7.99 (dd, J =9.2, 1.4 Hz, 1H), 7.37 ( dd, J = 9.3, 2.6 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 4.34 (s, 2H), 3.90 (s, 3H); MS (CIAD ^- ) m/z 404.6 (MH) ^- .

Example 145: 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ , 2,5-thiadiazolidin-1,1,3-trione (Compound 244)

Example 145A: 5-{3-(benzyloxy)-7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoronaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A 20 ml microwave tube was filled with the product from Example 143A (200 mg, 0.441 mmol) and N,N -dimethylformamide (3 ml). After that, 2-cyclopropylacetaldehyde and acetic acid (0.126 ml, 2.205 mmol) were added and the reaction was stirred for 5 minutes at ambient temperature. Sodium cyanoborohydride (166 mg, 2.65 mmol) was then added. The mixture was stirred at ambient temperature overnight. The mixture was partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was extracted with ethyl acetate (2×3 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (5 ml) and dried over sodium sulfate. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (23 mg, 0.044 mmol, 10% yield) . MS (CIAD ^- ) m / z 520 [MH] ^- .

Example 145B: 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ^6.2 ,5-thiadiazolidin-1,1,3-trione

A 50 ml round bottom flask was filled with the product of Example 145A (20 mg, 0.038 mmol), 1,2,3,4,5-pentamethylbenzene (17.05 mg, 0.115 mmol) and methylene chloride (3 ml). The reaction mixture was purged with nitrogen for 5 minutes. The heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.192 ml, 0.192 mmol) in dichloromethane was added dropwise over 5 minutes. The reaction mixture was stirred at -78°C for 30 minutes. Ethyl acetate (1 ml) and methanol (0.2 ml) were added and the reaction mixture was heated to ambient temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (2 mg, 0.046 mmol, 12% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.01 (s, 1H), 7.76 (s, 3H), 7.09 (s, 1H), 6.53 (d, J = 12.7 Hz, 1H), 4.49 (s, 2H), 4.18 (s, 2H), 4.10 (s, 2H), 3.32-3.25 (m, 2H), 1.59 (k, J = 7.7, 7.3 Hz, 2H), 0.77 (dd, J = 8.8, 4.3 Hz, 1H), 0.51-0.42 (m, 2H), 0.19-0.11 (m, 2H); MS (CIAD ^- ) m/z 430 [MH] ^- .

Example 146: 5-{1-Fluoro-3-hydroxy-7-[(1 E )-3-methoxyprop-1-en-1-yl]naphthalene-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine -1,1,3-trione (Compound 245)

To a solution of the product of example 128A (0.170 g, 0.453 mmol) was added dioxane:water (3:1, 4.5 ml, 0.1 M) followed by ( E )-2-(3-methoxyprop-1-en- 1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.179 g, 0.906 mmol) and potassium carbonate (0.188 g, 1.359 mmol). This suspension was purged with N ₂ for 10 minutes and then 1,1'-bis(di- tert -butylphosphino)ferrocene palladium dichloride (0.00295 g, 0.00453 mmol) was added. Blowing was continued for 5 minutes, and then the biphasic suspension was heated at 80°C for 12 hours. The mixture was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure to give the crude title compound, which was purified by reverse phase HPLC (Phenomenex® C8(2) Luna® 5 µm AXIA™ 150 x 30 mm column, 3-100% gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) over 17 minutes at a flow rate of 50 ml/minute to give the title compound (0.137 g, 0.374 mmol, 83%) ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.80 (s, 1H), 7.69 (d, J =1.4 Hz, 2H), 7.05 (d, J =1.2 Hz, 1H), 6.77 (d, J =16.0 Hz, 1H), 6.44 (dt, J =16.0, 5.8 Hz, 1H), 4.08 (d, J =5 .9 Hz, 4H), 3.30 (s, 3H), MS (APCI ^- ) m/z 365 [MH] ^- .

Example 147 5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 246)

The title compound was prepared from the compound of Example 1H and 1-bromo-2-ethoxyethane using the methods described for Example 83. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.31 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.24-7.17 (m, 2H), 7.07 (s, 1H), 4.48 (s, 2H), 4.22-4.17 (m, 2H), 3.78-3.72 (m, 2H), 3.52 (k, J = 7.0 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H); MS (CIAD ^- ) m/z 382.8 (MH) ^- .

Example 148 5-[1-Fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 247)

The title compound was prepared from the compound of Example 1H and 1-bromo-3-methoxypropane using the methods described for Example 83. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.20 (s, 1H), 7.74-7.67(m, 1H), 7.23-7.14(m, 2H), 7.06(s, 1H), 4.43(s, 2H), 4.12 (t, J =6.4 Hz, 2H), 3.51 (t, J =6.3 Hz, 2H), 3.26 (s, 2H), 2.00 (n, J =6.4 Hz , 2H); MS (CIAD ^- ) m/z 382.9 (MH) ^-

^Example 149 _ ^_ _ ,1,3-trione (Compound 248)

Example 149A: 5-[3-(benzyloxy)-7-(1,1-dioxo-1,2,3,6-tetrahydro-1 λ ⁶ -thiopyran-4-yl)-1-fluoronaphthalen-2-yl] -1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To the product of Example 1G (180 mg, 0.698 mmol) in a 20 mL microwave tube were added dioxane (2 mL), 2 M aqueous sodium carbonate (0.806 mL, 1.612 mmol) and tetrakis(triphenylphosphine)palladium (0) (62, 1 mg, 0.054 mmol). The mixture was bubbled N ₂ for 5 minutes and heated to 100°C during the night. The reaction mixture was cooled to ambient temperature and the volatiles were removed under reduced pressure. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) in for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (156 mg, 0.302 mmol, 56% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.91 (d, J =2.0 Hz, 1H), 7.84 (dd, J =8.8, 1.6 Hz, 1H), 7.72 (dd, J =8.7, 2.0 Hz, 1H), 7.52-7.45 (m, 2H), 7.42 (s, 1H), 7.39-7 .30 (m, 2H), 7.34-7.25 (m, 1H), 6.20-6.13 (m, 1H), 5.24 (s, 2H), 4.44 (s, 2H ), 3.90 (d, J =4.9 Hz, 2H), 3.50-3.47 (m, 1H), 3.35 (s, 1H), 3.13 (d, J =6, 4 Hz, 2H); MS (CIAD ^- ) m/z 515 [MH] ^- .

Example 149B: 5-[7-(1,1-dioxo-1 λ ⁶ -thian-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione

The product from example 149A (55 mg, 0.106 mmol) and 1,4-dioxane (2 ml) were added in 5% Pd/C (wet, 57 mg, 0.250 mmol) in a 20 ml Barnstead Hast C reactor and the mixture was stirred at 25° C for 37 hours at 74 psi. inch of hydrogen gas. The mixture was filtered under nitrogen and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) in for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (14 mg, 0.033 mmol, 31% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.78-7.69 (m, 2H), 7.48 (dd, J =8.6, 1.7 Hz, 1H), 7.10 (d, J =1.3 Hz, 1H), 4.55 (s, 2H), 3.89 (ddd, J =11.0, 4.1, 1.8 Hz, 2H), 3 .48-3.36 (m, 2H), 2.94 (tt, J =10.7, 3.9 Hz, 1H), 2.03-1.94 (m, 1H), 1.90-1 .76 (m, 1H), 1.68 (tk, J = 8.1, 4.0 Hz, 2H); MS (CIAD ^- ) m/z 427 [MH] ^- .

Example 150 5-[1-Fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 249 )

Example 150A: 5-[3-(Benzyloxy)-7-(5,6-dihydro-2H-pyran-3-yl)-1-fluoronaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione

To the product of example 1G (250 mg, 0.537 mmol) was added 1,4-dioxane (2 ml), 2-(5,6-dihydro- 2H- pyran-3-yl)-4,4,5,5-tetramethyl -1,3,2-dioxaborolane (147 mg, 0.698 mmol) and 2 M aqueous sodium carbonate solution (0.806 ml, 1.612 mmol). Tetrakis(triphenylphosphine)palladium (0) (62.1 mg, 0.054 mmol) was added and the reaction mixture was sparged with N ₂ for 5 minutes. The mixture was heated to 90°C and stirred overnight. The mixture was cooled to ambient temperature and the volatiles were removed under reduced pressure. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm x 25 mm). 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (146 mg, 0.312 mmol, 58% yield) . MS (CIAD ^- ) m/z 467 [MH] ^-

Example 150B: 5-[1-Fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

The product from Example 150A (55 mg, 0.117 mmol) and tetrahydrofuran (2 ml) were added in 5% Pd/C (wet, 54 mg, 0.236 mmol) in a 20 ml Barnstead Hast C reactor and the mixture was stirred at 25°C for 37 hours at 58 psi inch of hydrogen gas. The mixture was filtered under N ₂ and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) in for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (12 mg, 0.032 mmol, 23% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.79-7.70 (m, 2H), 7.47 (dd, J =8.6, 1.8 Hz, 1H), 7.10 (d, J =1.3 Hz, 1H), 4.52 (s, 2H), 3.42-3.30 (m, 2H), 3.20-3.05 (m, 3H) , 2.27-2.13 (m, 4H); MS (CIAD ^- ) m/z 379 [MH] ^-

Example 151 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 250)

The title compound was prepared from the compound of Example 1H and (bromomethyl)cyclopropane using the methods described for Example 83. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.36 (s, 1H), 7.71 (d, J =9.1 Hz, 1H), 7.20 (dd, J =9.0, 2.6 Hz, 1H), 7.17 (d, J =2.5 Hz, 1H ), 7.07 (s, 1H), 4.50 (s, 2H), 3.92 (d, J = 7.0 Hz, 2H), 1.27 (ddd, J = 12.4, 7, 6, 4.8 Hz, 1H), 0.64-0.54 (m, 2H), 0.40-0.32 (m, 2H); MS (CIAD ^- ) m/z 365 (MH) ^- .

Example 152: 5-(1-fluoro-3-hydroxy-7-{ [ 1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)-1 λ ^6.2 5-thiadiazolidin-1,1,3-trione (Compound 251)

In a 4 ml test tube, 5-{7-bromo-1-fluoro-3-[(2-methoxyethoxy)methoxy]naphthalen-2-yl}-2-[(2-methoxyethoxy)methyl]-1λ ⁶ ,2,5 -thiadiazolidin-1,1,3-trione (example 127A, 100 mg, 0.181 mmol, 1.0 eq.) and Pd SPhos G4 (7.20 mg, 9.07 μmol, 0.05 eq.) in N, N -dimethylacetamide (2 ml). ((1-( tert -Butoxycarbonyl)pyrrolidin-3-yl)methyl)zinc (II) iodide (3.30 ml, 0.363 mmol, 2.0 eq., 0.11 M in tetrahydrofuran) was added. The tube was purged with N ₂ , stoppered and heated to 65° C. overnight.

The residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 25% A, 0.5-8.0 min linear gradient 25 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-25% A, 9.1-10.0 minutes 5% A) to give t -butyl 3-[(8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-{5-[(2-methoxyethoxy)methyl]-1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin- 2-yl}naphthalen-2-yl)methyl]pyrrolidine-1-carboxylate (42.1 mg, 41% yield).

tert -butyl 3-[(8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-{5-[(2-methoxyethoxy)methyl]-1,1,4-trioxo-1λ ^6,2,5 -thiadiazolidin-2-yl}naphthalen-2-yl)methyl]pyrrolidine-1-carboxylate was suspended in 4 M HCl in dioxane (1 ml), stirred for 10 minutes and dried under nitrogen flow to give 5-{1-fluoro -3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.79-7.56 (m, 2H), 7.38 (dd, J =8.5, 1.7 Hz, 1H), 7.05 (s, 1H), 4.13 (s, 2H), 3.26-3.01 (m, 3H), 2.86-2.72 (m, 3H), 2.58-2, 52 (m, 1H), 2.05-1.84 (m, 1H), 1.67-1.48 (m, 1H); MS (ESI ⁺ ) m/z 380.3 (M+H) ⁺ .

5-{1-fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (25 mg, 0.07 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (1.0 ml). N -ethyl- N -isopropylpropane-2-amine (34 μl, 0.20 mmol, 3.0 eq.) was added, followed by trifluoroethyl trifluoromethanesulfonate (11 μl, 0.08 mmol, 1.2 eq.). The reaction mixture was stirred overnight at ambient temperature. The reaction was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compound (1 .1 mg, 4% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.74-7.68 (m, 2H), 7.41 (dd, J =8.6, 1.6 Hz, 1H), 7.09 (s, 1H), 4.18 (s, 2H), 3.56-3.33 (m, 2H), 2.87 (dd, J =31.7, 8.3 Hz, 6H) , 1.99-1.89 (m, 1H), 1.62-1.53 (m, 1H), 1.33-1.23 (m, 1H); MS (CIAD ⁺ ) m/z 462.1 [M+H] ⁺ .

Example 153: 5-(1-fluoro- 3 -hydroxy-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)-1 λ ^6.2 5-thiadiazolidin-1,1,3-trione (Compound 252)

In a 4 ml tube, the compound from Example 1G (91 mg, 0.196 mmol, 1.0 eq.) and SPhos Pd G4 (7.7 mg, 9.78 μmol, 0.05 eq.) in N,N -dimethylacetamide ( 2 ml). ((1-( tert -Butoxycarbonyl)piperidin-4-yl)methyl)zinc (II) iodide (2.445 ml, 0.391 mmol, 2.0 eq.) (0.16 M in tetrahydrofuran) was added. The tube was purged with N ₂ , stoppered and heated to 65° C. overnight.

The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 35% A, 0.5-8.0 min linear gradient 35 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-35% A, 9.1-10.0 minutes 35% A) to give t -butyl 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]methyl}piperidin-1- carboxylate (95.7 mg, 84% yield); MS (CIAD ⁺ ) m/z 601.4 [M+H ₂ O] ⁺ .

tert -butyl 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]methyl}piperidine -1-carboxylate was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (100 μl) was added. The reaction was stirred at ambient temperature until the reaction was complete according to HPLC/MS (column: Phenomenex® Luna® 5 µm, C8(2) 100 Å, 50 x 2.00 mm. A gradient of acetonitrile (A) in 0.1% acetate was used ammonium in water (B) at a flow rate of 2 ml/min (0-2.5 minutes linear gradient 0-100% A, 2.5-2.9 minutes linear gradient 100-0% A, 2.9-3, 0 minutes 0% A).Hold time 1.376 minutes). The volatiles were removed under a stream of nitrogen and the solid was dried in vacuo to give 5-{3-(benzyloxy)-1-fluoro-7-[(piperidin-4-yl)methyl]naphthalene-2-yl}-1λ ⁶ , 2,5-thiadiazolidin-1,1,3-trione.

5-{3-(benzyloxy)-1-fluoro-7-[(piperidin-4-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (50 mg, 0.10 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (1.0 ml). N -ethyl- N -isopropylpropan-2-amine (54 µl, 0.31 mmol, 3.0 eq.) was added followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (18 µl, 0.12 mmol, 1 .2 equiv.). The reaction was stirred overnight at ambient temperature. The reaction was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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/minute (0-0.5 minutes 15% A, 0.5-8.0 minutes linear gradient 15-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give 5-[3-( benzyloxy)-1-fluoro-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1, 3-trione (11.4 mg, 20% yield); MS (CIAD ⁺ ) m/z 566.1 [M+H] ⁺ .

5-[3-(benzyloxy)-1-fluoro-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl]-1λ ^6,2,5- thiadiazolidin-1,1,3-trione (11.4 mg, 0.020 mmol) and tetrahydrofuran (2 ml) were added in 5% Pd/C (wet JM#9) (6 mg, 0.026 mmol) in a 20 ml Barnstead Hast reactor C and stirred the mixture for 1.2 hours at 50 psi. inch of hydrogen and 25°C for 60 hours. The reaction was filtered and the solvent was removed under a stream of nitrogen. The residue was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.69-7.55 (m, 2H), 7.32 (dd, J =8.4, 1.7 Hz, 1H), 7.04 (s, 1H), 4.12 (s, 2H), 3.05 (q, J = 10.2 Hz, 2H), 2.85 (d, J = 11.4 Hz, 2H), 2.63 (d, J =6.7 Hz, 2H), 2.23 (dd, J =12.7, 10.4 Hz, 2H), 1.64-1.43 (m, 3H), 1 .31-1.06 (m, 2H); MS (CIAD ⁺ ) m/z 476.1 [M+H] ⁺ .

Example 154: 5-(1-Fluoro-3-hydroxy-7-{2-[methyl(2-methylpropyl)amino]ethoxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione (Compound 253)

Example 154A: 5-[3-(Benzyloxy)-7-(2,2-dimethoxyethoxy)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Cesium carbonate (Cs ₂ CO ₃ , 4.367 g, 13.42 mmol) and 2-bromo-1 ,1-Dimethoxyethane (2.268 g, 13.42 mmol) at 20°C. The mixture was then stirred for 12 hours at 50° C. under a nitrogen atmosphere. The reaction was quenched with water (20 ml) and acidified with HCl (1 N, aqueous solution) to pH=4. The resulting mixture was extracted with ethyl acetate (3 x 200 ml). The organic layer was washed with brine (700 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with methyl tert -butyl ether (100 ml) and filtered. The precipitate was collected and dried under high vacuum to give the title compound (2.3 g, 4.22 mmol, 90% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.95 (s, 1 H), 7.82 (d, J=8.80 Hz, 1 H), 7.52 (br. d, J=6.85 Hz, 2 H), 7.27-7.46 (m, 6 H), 5.24 (s, 1 H), 4.75 (s, 1 H), 4.52 (s, 1 H), 4.13 (d, J=5.01 Hz, 2 H), 3.38 (s, 5 H); MS (ESI ^- ) m/z 489 (MH) ^- .

Example 154B: 5-[7-(2,2-dimethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

To a mixture of 10% Pd-C (0.859 g, 8.07 mmol) in methanol (100 ml) was added the compound from Example 154A (2.2 g, 4.04 mmol) at 25°C, and then the mixture was stirred for 1 hours at 25°C under hydrogen balloon conditions (15 psi). The mixture was filtered through a bed of diatomaceous earth and the filtrate was concentrated under reduced pressure to give the title compound (1.5 g, 3.18 mmol, 79% yield), which was used in the next step without further purification. MS (ESI ^- ) m/z 399 (MH) ^- .

Example 154C: {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetaldehyde

To a solution of the compound from example 154B (1.5 g, 3.18 mmol) in acetone (10 ml) was added dropwise hydrochloric acid (6 N, aqueous solution) (10 ml, 60.0 mmol) at 20°C. Then the reaction mixture was heated at 60°C for 30 minutes. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC: Phenomenex® Luna® C18 column 10 µm, 50 x 250 mm, flow rate 80 ml/min, 30-100% acetonitrile gradient in water (0.048 M aqueous HCl)] and lyophilized to give the title compound (182 mg, 0.478 mmol, 15% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.31-10.52 (m, 1 H), 9.73 (s, 1 H), 7.75 (d, J=9 .13 Hz, 1 H), 7.16-7.30 (m, 2 H), 7.09 (s, 1 H), 5.01 (s, 2 H), 4.51 (s, 1 H ); MS (ESI ^- ) m/z 353 (MH) ^- .

Example 154D: 5-(1-fluoro-3-hydroxy-7-{2-[methyl(2-methylpropyl)amino]ethoxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trion

The compound from Example 154C (10 mg, 0.028 mmol) was dissolved in methanol (0.2 ml), followed by the addition of N ,2-dimethylpropan-1-amine (4.92 mg, 0.056 mmol) and acetic acid (8.47 mg , 0.141 mmol) and the resulting mixture was stirred for 30 minutes at room temperature. Then NaBH ₃ CN (3.55 mg, 0.056 mmol) was added. The mixture was stirred for 2 hours. The reaction mixture was purified by preparative HPLC on a Phenomenex® Luna® 10 µm C18 column (30 mm × 250 mm), eluted with a gradient of acetonitrile (A) and water (B) with 0.1% trifluoroacetic acid at a flow rate of 50 ml/minute ( 0-1 minute 0% A, 1-20 minutes linear gradient 20-100%) to give the title compound (6 mg, 34% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.75 (s, 1H), 9.00 (s, 1H), 7.74 (dd, J=9.1, 1.4 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.19 (dd, J=9.0, 2.5 Hz, 1H), 7.07 (s, 1H), 4.48 (t, J=5.1 Hz, 2H), 4.18 (s, 2H), 3.64 (m, 1H), 3.55 (m, 1H), 3.12 (m, 1H ), 2.98 (m, 1H), 2.91 (d, J=4.7 Hz, 3H), 2.11 (m, 1H), 0.97 (dd, J=6.6, 4, 1Hz, 6H); MS (APCI ⁺ ) m/z 426.0 (M+H) ⁺ .

Example 155 5-{1-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3 ^- trione (Compound 254)

Example 155A: 5-{3-(benzyloxy)-1-fluoro-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione

To a solution of the product of example 1H (100 mg, 0.249 mmol) in N,N -dimethylformamide (2 mL) was added 2-(bromomethyl)tetrahydrofuran (90 mg, 0.547 mmol) and cesium carbonate (178 mg, 0.547 mmol). The reaction mixture was heated to 65°C overnight. The reaction mixture was then cooled to ambient temperature and partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was further extracted with ethyl acetate (2×3 ml) and 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 residue was subjected to column chromatography (SiO ₂ , 10% methanol in dichloromethane) to give the title compound (35 mg, 0.072 mmol, 29% yield). MS (CIAD ^- ) m/z 485 [MH] ^- .

Example 155B: 5 - {1 - fluoro - 3 - hydroxy - 7 - [(oxolane - 2 - yl)methoxy]naphthalene - 2 - yl} - 1 λ ⁶ ,2,5 - thiadiazolidin - 1,1,3 - trione

The product from example 155A (55 mg, 0.117 mmol) and tetrahydrofuran (2 ml) were added in 5% Pd/C (wet, 54 mg, 0.236 mmol) in a 20 ml Barnstead Hast C reactor and the mixture was stirred at 25°C for 37 hours at 58 psi inch of hydrogen gas. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) in over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (12 mg, 0.032 mmol, 23% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.79-7.70 (m, 2H), 7.47 (dd, J =8.6, 1.8 Hz, 1H), 7.10 (d, J =1.3 Hz, 1H), 4.52 (s, 2H), 3.42-3.30 (m, 2H), 3.20-3.05 (m, 3H) , 2.27-2.13 (m, 4H); MS (CIAD ^- ) m/z 379 [MH] ^- .

Example 156 5-[1-Fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 255 )

Example 156A: 5-[3-(Benzyloxy)-7-(2,5-dihydrofuran-3-yl)-1-fluoronaphthalen-2-yl]-1 λ 6 ,2,5 ^- thiadiazolidin-1,1,3 -trione

To the product from Example 1G (120 mg, 0.258 mmol) was added 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (65.7 mg, 0.335 mmol) and 2 M aqueous sodium carbonate solution (0.387 ml, 0.774 mmol). Tetrakis(triphenylphosphine)palladium (0) (29.8 mg, 0.026 mmol) was added and the reaction mixture was sparged with N ₂ for 5 minutes. The mixture was heated to 100°C and stirred overnight. The reaction mixture was cooled to ambient temperature and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography (SiO ₂ , dry load with diatomaceous earth, 5% methanol in dichloromethane) to give the title compound (35 mg, 0.077 mmol, 30% yield). MS (CIAD ⁺ ) m/z 455 [M+H] ⁺

Example 156B: 5-[1-Fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

A 50 ml round bottom flask was filled with nitrogen followed by the addition of 5% Pd/C (23.18 mg, 0.218 mmol) and tetrahydrofuran (5 ml). Then a solution of the product of example 156A (40 mg, 0.083 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. The filtrate was concentrated under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (8 mg, 0.022 mmol, 30% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.74 (dd, J =8.5, 1.6 Hz, 2H), 7.47 (dd, J =8.6, 1 .8 Hz, 1H), 7.08 (s, 1H), 4.45 (s, 2H), 4.07 (t, J= 7.7 Hz, 1H), 3.99 (td, J = 8 .3, 4.6 Hz, 1H), 3.83 (k, J = 7.8 Hz, 1H), 3.67-3.59 (m, 1H), 3.56 (d, J = 7, 5 Hz, 1H), 2.36 (dtd, J =12.2, 7.6, 4.5 Hz, 1H), 2.09-1.92 (m, 1H); MS (CIAD ^- ) m/z 365 [MH] ^- .

Example 157: 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione (Compound 256)

In a 4 ml tube, the compound from Example 1G (78 mg, 0.16 mmol, 1.0 eq.) and SPhos Pd G4 (6.6 mg, 8.38 μmol, 0.05 eq.) were combined in N, N - dimethylacetamide (2 ml). ((1-( tert -Butoxycarbonyl)azetidin-3-yl)methyl)zinc (II) iodide (1.86 ml, 0.33 mmol, 2.0 eq.) (0.18 M in tetrahydrofuran) was added. The tube was purged with N ₂ , stoppered and heated to 65° C. overnight.

The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give t -butyl 3-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]methyl}azetidin-1- carboxylate (61.1 mg, 66% yield).

The residue was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (100 μl) was added. The reaction was stirred at ambient temperature until the reaction was complete according to HPLC/MS (column: Phenomenex® Luna® 5 µm, C8(2) 100 Å, 50 x 2.00 mm. A gradient of acetonitrile (A) in 0.1% acetate was used ammonium in water (B) at a flow rate of 2 ml/min (0-2.5 minutes linear gradient 0-100% A, 2.5-2.9 minutes linear gradient 100-0% A, 2.9-3, 0 minutes 0% A).Hold time 1.304 minutes). Volatile substances were removed in a stream of nitrogen, and 5-{7-[(azetidin-3-yl)methyl]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione was dried in vacuum.

5-{7-[(azetidin-3-yl)methyl]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (31, 9 mg, 0.07 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (0.5 ml). N -ethyl- N -isopropylpropan-2-amine (34 μl, 0.20 mmol, 3.0 eq.) was added, followed by cyclopropylsulfonyl chloride (8 μl, 0.08 mmol, 1.2 eq.). The reaction was stirred overnight at ambient temperature. The reaction was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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/minute (0-0.5 minutes 15% A, 0.5-8.0 minutes linear gradient 15-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give 5-[3-( benzyloxy)-7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (19.7 mg, 50% yield. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.80-7.69 (m, 2H), 7.56-7.53 (m, 2H), 7.44-7.25 (m, 5H), 5.23 (s, 2H), 4.12 (s, 2H), 3.95-3.88 (m, 2H), 3.72-3.65 (m, 2H), 3.08-3.02 (m, 2H), 3.01-2.92 (m, 1H), 2.74-2.67 (m, 1H), 1.07-0.94 (m, 2H ), 0.94-0.85 (m, 2H).

5-[3-(benzyloxy)-7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3 -trione (20 mg, 0.036 mmol) and solvent mixture of tetrahydrofuran (2 ml), methanol (1 ml) and dichloromethane (0.2 ml) were added in 5% Pd/C, wet (20 mg, 0.094 mmol) in 20 ml reactor Barnstead Hast C and stirred the mixture for 17 hours at 50 psi. inch of hydrogen and 25°C. HPLC analysis showed incomplete conversion (column: Supelco Ascentis® Express C18, 2.7 µm, fused-core silica, 4.6 x 150 mm. A gradient of acetonitrile (A) in 0.1% HClO ₄ in water (B ) at a flow rate of 1.5 ml/min (0-8 minutes linear gradient 10-90% A, 8-13 minutes 90% A, retention time 4.1 minutes) and continued hydrogenation for an additional 14 hours. consumption of starting material The reaction mixture was filtered and concentrated in a stream of nitrogen The residue was dissolved in dimethyl sulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 µm Waters XBridge™ C8 column (75 mm x 30 mm) A methanol gradient was used (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 ml/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A, 8 0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give the title compound (10.4 mg , yield 61%) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.74-7.60 (m, 2H), 7.36 (dd, J =8.4, 1, 7 Hz, 1H), 7.05 (s, 1H), 4.12 (s, 2H), 3.91 (s, 2H), 3.73-3.63 (m, 2H), 3.10- 2.91 (m, 3H), 2.75-2.67 (m, 1H), 1.11-0.99 (m, 2H), 0.95-0.80 (m, 2H); MS (ESI ⁺ ) m/z 470.5 [M+H] ⁺ .

Example 158: 5-(7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione (Compound 257)

In a 4 ml tube, the compound from Example 1G (91 mg, 0.196 mmol, 1.0 eq.) and SPhos Pd G4 (7.7 mg, 9.78 μmol, 0.05 eq.) in N,N -dimethylacetamide ( 2 ml). ((1-( tert -butoxycarbonyl)piperidin-4-yl)methyl)zinc (II) iodide (2.445 ml, 0.391 mmol, 2.0 eq.) (0.16 M in tetrahydrofuran) was added. The tube was purged with N ₂ , stoppered and heated to 65° C. overnight.

The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 35% A, 0.5-8.0 min linear gradient 35 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-35% A, 9.1-10.0 minutes 35% A) to give t -butyl 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]methyl}piperidin-1- carboxylate (95.7 mg, 84% yield). MS (CIAD ⁺ ) m/z 601.4 [M+H ₂ O] ⁺ .

tert -butyl 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]methyl}piperidine -1-carboxylate was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (100 μl) was added. The reaction was stirred at ambient temperature until the reaction was complete according to HPLC/MS (column: Phenomenex® Luna® 5 µm, C8(2) 100 Å, 50 x 2.00 mm. A gradient of acetonitrile (A) in 0.1% acetate was used ammonium in water (B) at a flow rate of 2 ml/min (0-2.5 minutes linear gradient 0-100% A, 2.5-2.9 minutes linear gradient 100-0% A, 2.9-3, 0 minutes 0% A).Hold time 1.376 minutes). Volatile substances were removed in a stream of nitrogen, and 5-{3-(benzyloxy)-1-fluoro-7-[( ^piperidin -4-yl)methyl]naphthalen-2-yl}-1λ ,1,3-trione was dried in vacuum.

5-{3-(benzyloxy)-1-fluoro-7-[(piperidin-4-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (31 .9 mg, 0.07 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (0.5 ml). N -ethyl- N -isopropylpropan-2-amine (34 μl, 0.20 mmol, 3.0 eq.) was added, followed by cyclopropylsulfonyl chloride (8 μl, 0.08 mmol, 1.2 eq.). The reaction was stirred overnight at ambient temperature. The reaction was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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/minute (0-0.5 minutes 15% A, 0.5-8.0 minutes linear gradient 15-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give 5-[3-( benzyloxy)-7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (19.2 mg, 50% yield.

Pure pentamethylbenzene (10.1 mg, 0.07 mmol, 2.0 eq.) was added to the reaction tube containing 5-[3-(benzyloxy)-7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl }-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione. Added dichloromethane (1 ml), closed the tube with a stopper and cooled to -78°C. BCl ₃ (1 M in dichloromethane, 100 μl, 0.1 mmol, 3.0 eq.) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour. 100 μl of 1:1 methanol/dichloromethane was added. The mixture was dried under nitrogen flow and reconstituted in dimethylsulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give the title compounds (8.8 mg, 52% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.73-7.68 (m, 2H), 7.39 (dd, J =8.4, 1.7 Hz, 1H), 7.09 (s, 1H), 4.17 (s, 2H), 3.65-3.55 (m, 2H), 2.84-2.76 (m, 2H), 2.72 (d, J = 7.1 Hz, 2H), 1.73-1.67 (m, 2H), 1.33-1.25 (m, 2H), 1.03-0.96 (m, 2H), 0 .96-0.89 (m, 2H).

Example 159 5-[1-Fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1 λ 6 ,2,5- ^{thiadiazolidin} -1,1,3-trione (Compound 258 )

In a 4 ml tube, the NiCl ₂ adduct of dimethoxyethane (1.44 mg, 0.006 mmol, 0.12 eq.) and 4,4'-di -tert -butyl-2,2'-dipyridyl (1.75 mg, 0.006 mmol , 0.12 eq.) in N,N -dimethylacetamide (0.5 ml). 5-{7-Bromo-1-fluoro-3-[(2-methoxyethoxy)methoxy]naphthalen-2-yl}-2-[(2-methoxyethoxy)methyl]-1λ ⁶ ,2,5-thiadiazolidin-1 was added ,1,3-trione (Example 127A, 30 mg, 0.05 mmol, 1.0 eq.), (1-( tert -butoxycarbonyl)pyrrolidin-2-yl)potassium trifluoroborate (22.6 mg, 0.08 mmol, 2.0 eq.) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium (1+), 2-(2-pyridyl)pyridine, hexafluorophosphate (5 .0 mg, 0.005 mmol, 0.03 eq.), followed by dioxane (0.5 ml). 2,6-dimethylpyridine (10 μl, 0.087 mmol, 1.6 eq.) was added and the reaction mixture was irradiated overnight using a 450 nm diode photoreactor.

The reaction was filtered and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 35% A, 0.5-8.0 min linear gradient 35 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-35% A, 9.1-10.0 minutes 35% A) to give t -butyl 2-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl}pyrrolidin- 1-carboxylate. tert -butyl 2-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl }pyrrolidine-1-carboxylate was treated with 1 4 M HCl in dioxane (1 ml) and stirred until HPLC/MS was complete (column: Phenomenex® Luna® 5 µm, C8(2) 100 Å, 50 × 2.00 mm. A gradient was used acetonitrile (A) in 0.1% ammonium acetate in water (B) at a flow rate of 2 ml/min (0-2.5 minutes linear gradient 0-100% A, 2.5-2.9 minutes linear gradient 100- 0% A, 2.9-3.0 minutes 0% A. Hold time 0.93 minutes). The reaction was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (4 mg, 20% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.99-7.91 (m, 1H), 7.80 (d, J =8.6 Hz, 1H), 7.55 ( dd, J = 8.7, 1.8 Hz, 1H), 7.18-6.98 (m, 1H), 4.63-4.55 (m, 1H), 4.15 (s, 2H) , 3.39-3.20 (m, 2H), 2.46-2.31 (m, 1H), 2.20-1.95 (m, 3H); MS (ESI ^- ) m/z 364.0 (MH) ⁺ .

Example 160: 5-(7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione (Compound 259)

In a 4 ml tube, the compound from example 1G (98 mg, 0.21 mmol, 1.0 eq.) and SPhos Pd G4 (7.2 mg, 10.5 μmol, 0.05 eq.) were combined in N, N - dimethylacetamide (1 ml). ((1-( tert -Butoxycarbonyl)piperidin-3-yl)methyl)zinc (II) iodide (2.81 ml, 0.42 mmol, 2.0 eq.) (0.15 M in tetrahydrofuran) was added. The tube was purged with N ₂ , stoppered and heated to 65° C. overnight. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 35% A, 0.5-8.0 min linear gradient 35 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-35% A, 9.1-10.0 minutes 35% A) to give t -butyl 3-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]methyl}piperidin-1- carboxylate (62.1 mg, 51% yield).

tert -butyl 3-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]methyl}piperidine -1-carboxylate was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (100 μl) was added. The reaction mixture was stirred at ambient temperature until completion of the reaction according to HPLC/MS (column: Phenomenex® Luna® 5 μm, C8(2) 100 Å, 50 x 2.00 mm. A gradient of acetonitrile (A) at 0.1% was used ammonium acetate in water (B) at a flow rate of 2 ml/min (0-2.5 minutes linear gradient 0-100% A, 2.5-2.9 minutes linear gradient 100-0% A, 2.9-3 .0 minutes 0% A) Hold time 1.391 minutes). Volatiles were removed in a stream of nitrogen, and 5-{3-(benzyloxy)-1-fluoro-7-[(piperidin-3-yl)methyl]naphthalen-2-yl} ^-1λ ,1,3-trione was dried in vacuum.

5-{3-(benzyloxy)-1-fluoro-7-[(piperidin-3-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (31 .9 mg, 0.07 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (0.5 ml). N -ethyl- N -isopropylpropan-2-amine (34 μl, 0.20 mmol, 3.0 eq.) was added, followed by cyclopropylsulfonyl chloride (8 μl, 0.08 mmol, 1.2 eq.). The reaction was stirred overnight at ambient temperature. The reaction was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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/minute (0-0.5 minutes 15% A, 0.5-8.0 minutes linear gradient 15-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give 5-[3-( benzyloxy)-7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (18.2 mg, 47% yield. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.81-7.68 (m, 2H), 7.59-7.49 (m, 2H), 7.48-7.25 (m, 5H), 5.23 (s, 2H), 4.12 (d, J =3.4 Hz, 2H), 3.40 (d, J =11.4 Hz, 2H), 2.86 -2.55(m, 5H), 1.90-1.81(m, 1H), 1.75-1.60(m, 2H), 1.46-1.37(m, 1H), 1 .26-1.05 (m, 1H), 0.99-0.92 (m, 2H), 0.87-0.77 (m, 2H).

Pure pentamethylbenzene (10.1 mg, 0.07 mmol, 2.0 eq.) was added to the reaction tube containing 5-[3-(benzyloxy)-7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl }-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione. Added dichloromethane (1 ml), closed the tube with a stopper and cooled to -78°C. BCl ₃ (1 M in dichloromethane, 100 μl, 0.1 mmol, 3.0 eq.) was added dropwise. The reaction mixture was stirred at -78°C for 1 hour. 100 μl of 1:1 methanol/dichloromethane was added. The mixture was dried under nitrogen flow and reconstituted in dimethyl sulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give the title compounds (8.8 mg, 52% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.75-7.68 (m, 2H), 7.41 (dd, J =8.5, 1.8 Hz, 1H), 7.10 (s, 1H), 4.17 (s, 2H), 3.49 (t, J =14.0 Hz, 2H), 2.91-2.81 (m, 1H), 2.75 -2.58 (m, 2H), 1.94-1.89 (m, 1H), 1.81-1.70 (m, 2H), 1.52-1.45 (m, 1H), 1 .22-1.15 (m, 1H), 1.05-0.95 (m, 2H), 0.91-0.85 (m, 2H).

Example 161 5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 260)

To a suspension of the compound from example 1H (200 mg, 0.497 mmol) in acetonitrile (1.2 ml) was added a solution of potassium hydroxide (558 mg, 9.94 mmol) in water (1.2 ml). After that, the mixture was cooled to -78°C and diethyl (bromodifluoromethyl)phosphonate (177 μl, 0.994 mmol) was added in one part to the frozen solution. After warming to ambient temperature, the reaction was stirred for 15 minutes, diluted with ethyl acetate (10 ml) and quenched with 1 M HCl (20 ml). The resulting layers were separated. The organic layer was washed with brine (2×10 ml), dried over sodium sulfate, filtered and concentrated in vacuo (14 mbar, 36°C) to give 191 mg of 5-[3-(benzyloxy)-7-(difluoromethoxy)-1 -fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione which was suspended with 1,2,3,4,5-pentamethylbenzene (188 mg, 1.27 mmol) in dichloromethane (2.1 ml) and cooled to -78°C. A solution of boron trichloride (844 μl, 0.844 mmol, 1.0 M in dichloromethane) was added dropwise over 5 minutes. After 15 minutes, the reaction was quenched with anhydrous methanol (205 μl, 5.07 mmol) and the mixture was heated to ambient temperature under nitrogen. The volatiles were removed to give a residue which was dissolved in dimethylsulfoxide:methanol (1:1, 3 mL) and purified by reverse phase HPLC [Phenomenex® Luna® 10 μM C18(2) 100 Å, AX (00G-4253- U0-AX), 250 x 30 mm, 50 ml/min, 1 injection, 5% → 95% acetonitrile/water (with 0.1% trifluoroacetic acid) for 15 minutes, monitored/obtained at 205 nm] to give the indicated in the title compound (51.8 mg, 0.143 mmol, 34% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.73 (dd, J =9.3, 1.2 Hz, 1H), 7.60 (d, J =2.2 Hz, 1H ), 7.30 (dd, J =9.3, 2.5 Hz, 1H), 7.09 (s, 1H), 6.91 (t, J _HF =74.4 Hz, 1H), 4, 55 (s, 2H); MS (ESI ^- ) m/z 361 [MH] ^- .

Example 162: 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione (Compound 261)

In a 4 ml test tube, 5-{7-bromo-1-fluoro-3-[(2-methoxyethoxy)methoxy]naphthalen-2-yl}-2-[(2-methoxyethoxy)methyl]-1λ ⁶ ,2,5 -thiadiazolidin-1,1,3-trione (example 127A, 100 mg, 0.181 mmol, 1.0 eq.) and Pd SPhos G4 (7.20 mg, 9.07 μmol, 0.05 eq.) in N, N -dimethylacetamide (2 ml). ((1-( tert -Butoxycarbonyl)pyrrolidin-3-yl)methyl)zinc (II) iodide (3.30 ml, 0.363 mmol, 2.0 eq., 0.11 M in tetrahydrofuran) was added. The tube was purged with N ₂ , stoppered and heated to 65° C. overnight. The residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 25% A, 0.5-8.0 min linear gradient 25 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-25% A, 9.1-10.0 minutes 5% A) to give t -butyl 3-({8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl}methyl )pyrrolidine-1-carboxylate (42.1 mg, 41% yield).

tert -butyl 3-({8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2- yl}methyl)pyrrolidine-1-carboxylate was suspended in 4 M HCl in dioxane (1 ml), stirred for 10 minutes and dried under nitrogen flow to give 5-{1-fluoro-3-hydroxy-7-[(pyrrolidine- 3-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.79-7.56 (m, 2H), 7.38 (dd, J =8.5, 1.7 Hz, 1H), 7.05 (s, 1H), 4.13 (s, 2H), 3.26-3.01 (m, 3H), 2.86-2.72 (m, 3H), 2.58-2, 52 (m, 1H), 2.05-1.84 (m, 1H), 1.67-1.48 (m, 1H); MS (ESI ⁺ ) m/z 380.3 (M+H) ⁺ .

5-{1-fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (32 mg, 0.08 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (1.0 ml). N -ethyl- N -isopropylpropan-2-amine (44 μl, 0.25 mmol, 3.0 eq.) was added, followed by cyclopropylsulfonyl chloride (10 μl, 0.10 mmol, 1.2 eq.). The reaction was stirred overnight at ambient temperature. The reaction was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compound (4 .6 mg, 11% yield. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.71-7.64 (m, 2H), 7.38 (d, J =7.6 Hz, 1H), 7.04 ( s, 1H), 4.12 (s, 2H), 3.49-3.19 (m, 4H), 3.02-2.95 (m, 1H), 2.87-2.78 (m, 1H), 1.67-1.55 (m, 1H), 1.16 (d, J =17.7 Hz, 4H), 0.97-0.87 (m, 3H); MS (ESI ^- ) m/z 483.0 [MH] ⁺ .

Example 163 5-{1-Fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3 ^- trione (Compound 262)

In a 4 ml test tube, 5-{7-bromo-1-fluoro-3-[(2-methoxyethoxy)methoxy]naphthalen-2-yl}-2-[(2-methoxyethoxy)methyl]-1λ ⁶ ,2,5 -thiadiazolidin-1,1,3-trione (example 127A, 100 mg, 0.181 mmol, 1.0 eq.) and Pd SPhos G4 (7.20 mg, 9.07 μmol, 0.05 eq.) in N, N -dimethylacetamide (2 ml). ((1-( tert -Butoxycarbonyl)pyrrolidin-3-yl)methyl)zinc (II) iodide (3.30 ml, 0.363 mmol, 2.0 eq., 0.11 M in tetrahydrofuran) was added. The tube was purged with N ₂ , stoppered and heated to 65° C. overnight. The residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 25% A, 0.5-8.0 min linear gradient 25 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-25% A, 9.1-10.0 minutes 5% A) to give t -butyl 3-[(8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-{5-[(2-methoxyethoxy)methyl]-1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin- 2-yl}naphthalen-2-yl)methyl]pyrrolidine-1-carboxylate.

Sample tert -butyl 3-[(8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-{5-[(2-methoxyethoxy)methyl]-1,1,4-trioxo-1λ ⁶ .2, 5-thiadiazolidin-2-yl}naphthalen-2-yl)methyl]pyrrolidine-1-carboxylate was suspended in 4 M HCl in dioxane (1 ml), stirred for 10 minutes and dried under nitrogen flow. The residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (2.1 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.79-7.56 (m, 2H), 7.38 (dd, J =8.5, 1.7 Hz, 1H), 7.05 (s, 1H), 4.13 (s, 2H), 3.26-3.01 (m, 3H), 2.86-2.72 (m, 3H), 2.58-2, 52 (m, 1H), 2.05-1.84 (m, 1H), 1.67-1.48 (m, 1H); MS (ESI ⁺ ) m/z 380.3 (M+H) ⁺ .

Example 164: 5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ,2,5 ^- thiadiazolidin-1,1,3-trione (Compound 263)

A microwave tube was filled with the product of Example 128A (80 mg, 0.213 mmol), 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54, 3 mg, 0.277 mmol), 1,1'-bis(di- tert -butylphosphino)ferrocene palladium dichloride (2.085 mg, 3.20 µmol) and potassium carbonate (88 mg, 0.640 mmol). 1,4-dioxane (2 ml) and water (1 ml) were added successively. The reaction mixture was purged with N ₂ for 5 minutes and stirred at 60°C overnight. The reaction was then cooled to ambient temperature and partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was extracted with ethyl acetate (2×3 ml), the combined organic layers were washed with saturated aqueous ammonium chloride (5 ml) and dried over sodium sulfate. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (40 mg, 0.110 mmol, 52% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.76 (s, 1H), 7.79 (s, 2H), 7.64 (s, 1H), 7.12 (s, 1H), 6.65 (t, J =2.1 Hz, 1H), 5.01 (td, J =4.7, 2.0 Hz, 2H), 4.77 (td, J =4.7 , 1.9 Hz, 2H), 4.50 (s, 2H); MS (CIAD ^- ) m/z 363 [MH] ^- .

Example 165: 5-[7-(3,6-dihydro-2H- pyran -4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (Compound 264)

A microwave tube was filled with the product of Example 128A (80 mg, 0.213 mmol), 2-(3,6-dihydro- 2H- pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2 -dioxaborolan (58.2 mg, 0.277 mmol), potassium carbonate (88 mg, 0.640 mmol) and 1,1'-bis(di- tert -butylphosphino)ferrocene palladium dichloride (2.085 mg, 3.20 µmol). 1,4-dioxane (2 ml) and water (1 ml) were added successively, and the reaction mixture was purged with N ₂ for 5 minutes and stirred at 60° C. overnight. The mixture was then cooled to ambient temperature and partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was extracted with ethyl acetate (2×3 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (5 ml) and dried over sodium sulfate. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (37 mg, 0.098 mmol, 46% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.65 (s, 1H), 7.82 (s, 1H), 7.79-7.71 (m, 2H), 7, 10 (s, 1H), 6.45 (dc, J =2.9, 1.4 Hz, 1H), 4.49 (s, 2H), 4.27 (c, J =2.8 Hz, 2H ), 3.87 (t, J =5.5 Hz, 2H), 2.56 (ddd, J =8.9, 5.7, 2.9 Hz, 2H); MS (CIAD ^- ) m/z 377 [MH] ^- .

Example 166: 5-[7-(2,5-dihydro-1 H -pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (Compound 265)

The product from Example 123A (75 mg, 0.135 mmol) and 1,2,3,4,5-pentamethylbenzene (60.3 mg, 0.406 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (2 ml) was added, and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.406 ml, 0.406 mmol) in dichloromethane was added dropwise over 5 minutes. Subsequently, the reaction was quenched at -78°C with ethanol (0.1 ml) and dichloromethane (0.9 ml), and then slowly warmed up to ambient temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0.1% ammonium acetate in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (8 mg, 0.022 mmol, 16% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.78 (broad, 3H), 7.09 (d, J =1.3 Hz, 1H), 6.56 (t, J = 2.1 Hz, 1H), 4.49 (k, J =2.4 Hz, 2H), 4.19 (k, J =2.4 Hz, 2H), 4.10 (s, 2H); MS (CIAD ⁺ ) m/z 364 [M+H] ⁺ .

Example 167 5-[1-Fluoro-3-hydroxy-7-(pyridin-3-yl)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 266 )

A microwave tube was filled with the product of Example 128A (80 mg, 0.213 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (56.8 mg, 0.277 mmol ), potassium carbonate (88 mg, 0.640 mmol) and palladium 1,1'-bis(di -tert -butylphosphino)ferrocene dichloride (2.085 mg, 3.20 µmol). 1,4-dioxane (2 ml) and water (1 ml) were added successively. The reaction mixture was purged with N ₂ for 5 minutes and stirred at 60°C overnight. The reaction was then cooled to ambient temperature and partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was extracted with ethyl acetate (2×3 ml). The combined organic layers were washed with saturated aqueous ammonium chloride (5 ml) and dried over sodium sulfate. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (26 mg, 0.07 mmol, 33%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.53 (s, 1H), 9.20 (s, 1H), 8.73 (d, J =5.1 Hz, 1H) , 8.60-8.55(m, 1H), 8.31(s, 1H), 7.97-7.92(m, 1H), 7.80(dd, J =8.1.5, 1 Hz, 1H), 7.17 (s, 1H), 4.33 (s, 2H); MS (CIAD ^- ) m/z 372 [MH] ^- .

Example 168: 5-{7-[(azetidin-3-yl)methyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3- ^trione ( Compound 267)

5-(7-Bromo-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (50 mg, 0.133 mmol, 1, 0 eq., example 128A) and Pd SPhos G4 (5.29 mg, 6.66 μmol, 0.05 eq.) in N,N -dimethylacetamide (1 ml). ((1-( tert -Butoxycarbonyl)azetidin-3-yl)methyl)zinc (II) iodide (1.481 ml, 0.267 mmol, 2.0 eq.) (0.18 M in tetrahydrofuran) was added. The reaction was purged with N ₂ , stoppered and heated to 65° C. overnight. The residue was purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give t -butyl 3-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]methyl}azetidine-1-carboxylate.

The residue was dissolved in 1 ml dichloromethane and 100 μm trifluoroacetic acid was added. The reaction was stirred for 10 minutes at ambient temperature. Volatiles were removed in a stream of nitrogen. The residue was reconstituted in dimethylsulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (7 mg, 14% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.73 7.62 (m, 2H), 7.32 (dd, J =8.5, 1.7 Hz, 1H), 7 .08 (d, J = 1.5 Hz, 1H), 4.14 (s, 2H), 4.02 3.94 (m, 2H), 3.80 3.64 (m, 2H), 3, 21 3.14 (m, 1H), 3.06 (d, J =7.8 Hz, 2H); MS (ESI ⁺ ) m/z 366.3 (M+H) ⁺ .

Example 169: N- (2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene- 2-yl]amino}acetamide (Compound 268)

To a solution of the product of Example 181 (0.033 g, 0.089 mmol) and 2-cyclopropylethanamine hydrochloride (0.013 g, 0.107 mmol) in dimethylformamide (0.6 mL) was added 1-[bis(dimethylamino)methylene] -1H -1.2, 3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (0.048 g, 0.125 mmol) followed by N,N -diisopropyethylamine (0.062 ml, 0.357 mmol). After 5 minutes, the reaction mixture was quenched with methanol (0.5 ml) and then filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm Waters XBridge™ C18 OBD column, 30 x 100 mm, flow rate 40 ml/min, gradient 3-30% methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.028 g, 0.062 mmol, 69.1% yield). ¹ H NMR (400 MHz, -d ₆ ) δ ppm 7.95 (t, J =5.8 Hz, 1H), 7.47 (dd, J =8.9, 1.6 Hz, 1H ), 7.00 (dd, J =8.9, 2.3 Hz, 1H), 6.90 (d, J =1.2 Hz, 1H), 6.55 (d, J =2.4 Hz , 1H), 4.08 (s, 2H), 3.68 (s, 2H), 3.19-3.09 (m, 2H), 1.25 (q, J = 7.0 Hz, 2H) , 0.66-0.51 (m, 1H), 0.35-0.23 (m, 2H), -0.04--0.09 (m, 2H); MS (ESI ^- ) m/z 435 [MH] ^- .

Example 170: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} -N -methylbutanamide (Compound 269)

To a suspension of the product of Example 1H (0.200 g, 0.497 mmol) and cesium carbonate (0.486 g, 1.491 mmol) in dimethylformamide (2 ml) was added tert -butyl 4-bromobutanoate (0.176 ml, 0.994 mmol) and the resulting mixture was heated to 60 °C. After 2 hours the reaction mixture was cooled to ambient temperature, quenched with 1 M hydrochloric acid (2 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The organic layers were combined and washed with saturated aqueous ammonium chloride (4×1 mL), then 4:1 brine/1M hydrochloric acid, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give tert -butyl 4-{ [6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanoate, which was used without purification for next reaction. MS (CIAD ^- ) m/z 543 [MH] ^- .

To a solution of crude tert -butyl 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl] hydroxy}butanoate (0.271 g, 0.497 mmol) and pentamethylbenzene (0.147 g, 0.994 mmol) in dichloromethane (5.4 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (2.98 ml, 1 M, 2, 98 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (2 ml) followed by water (2 ml), warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3×3 ml). The solid was washed with ethyl acetate (3×3 ml) and the filtrate was concentrated under reduced pressure to give a solid. The new solid was triturated with acetonitrile (2 x 2 mL) and the filtrate concentrated under reduced pressure to give 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ .2.5 -thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanoic acid as a solid, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 397 [MH] ^- .

Into a solution of the product of crude 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanoic acid (1 ml, 0.249 mmol) in dimethylformamide (1 ml) was added a solution of methylamine in tetrahydrofuran (0.746 ml, 2 M, 1.49 mmol), followed by 1-[bis(dimethylamino)methylene]-1 H -1.2 ,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (0.132 g, 0.348 mmol). After 5 minutes, the reaction mixture was quenched with methanol (0.5 ml), then the resulting solution was filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-35% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0146 g, 0.034 mmol, 13.8% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.64 (dd, J =9.1, 1.4 Hz, 1H), 7.15 (d, J =2.6 Hz, 1H), 7.15-7.08 (m, 1H), 7.01 (s, 1H), 4.11 (s, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.59 (s, 2H), 2.48 (t, J =7.2 Hz, 2H), 2.00 (n, J =6.8 Hz, 2H); MS (ESI ^- ) m/z 410 [MH] ^- .

Example 171: N -ethyl- N '-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene- 2-yl]oxy}ethyl)urea (Compound 270)

Isocyanatoethane (10.80 mg, 0.152 mmol) in N,N -dimethylformamide (0.2 ml) and sodium carbonate (26.8 mg, 0.253 mmol). The mixture was stirred at ambient temperature for 30 minutes, filtered through a glass microfiber separator filter, and purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 µm column, 50 x 100 mm, flow rate 140 ml/min, 5-100 % gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide)] to give the title compound (10 mg, 0.023 mmol, 27.8% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.74 (br s, 1H), 8.50 (s, 1H), 7.67 (d, J =8 Hz, 1H) , 7.19 (d, J =2 Hz, 1H), 7.14 (dd, J =8.2 Hz, 1H), 7.04 (s, 1H), 6.12 (t, J =8 Hz , 1H), 5.99 (t, J =8 Hz, 1H), 4.10 (s, 2H), 4.05 (t, J =8 Hz, 2H), 3.43 (m, 2H), 3.02 (k, J =8 Hz, 2H), 0.98 (t, J =8 Hz, 3H), MS (ESI-) m / z 425 (MH) ^- .

Example 172 5-{1-Fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3 ^- trione (Compound 271)

Example 172A: 5-{3-(Benzyloxy)-1-fluoro-7-[(oxan-3-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione

To a solution of the product of Example 1H (120 mg, 0.298 mmol) in N,N -dimethylformamide (2 mL) was added 3-(bromomethyl)tetrahydro-2H - pyran (117 mg, 0.656 mmol) and cesium carbonate (214 mg, 0.656 mmol ). The reaction mixture was heated to 80°C for 3 hours. The reaction was then cooled to ambient temperature and partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was further extracted with ethyl acetate (2×3 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 residue was subjected to column chromatography (SiO ₂ , 10% methanol in dichloromethane) to give the title compound (89 mg, 0.178 mmol, 60% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (dd, J =8.9, 1.4 Hz, 1H), 7.59-7.53 (m, 2H), 7.39-7.34 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.18 (m, 3H), 5.22 (s, 2H), 4, 09 (s, 2H), 3.98 (dd, J =6.6, 3.8 Hz, 2H), 3.95-3.90 (m, 1H), 3.34-3.28 (m, 2H), 3.79-3.72 (m, 1H), 3.31 (dd, J =11.1, 9.1 Hz, 1H), 2.09-2.01 (m, 1H), 1 .89 (dd, J =12.9, 4.3 Hz, 1H), 1.63 (dt, J =13.0, 3.9 Hz, 1H), 1.59-1.48 (m, 1H ), 1.48-1.38 (m, 1H); MS (CIAD ^- ) m / z 499 [MH] ^- .

Example 172B: 5 - {1 - fluoro - 3 - hydroxy - 7 - [(oxan - 3 - yl)methoxy]naphthalene - 2 - yl} - 1 λ ⁶ ,2,5 - thiadiazolidin - 1,1,3 - trione

The product from example 172A (87 mg, 0.174 mmol) and pentamethylbenzene (51.5 mg, 0.348 mmol) in a 250 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (50 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.695 ml, 0.695 mmol) in dichloromethane was added dropwise over 5 minutes. After stirring for 30 minutes, the reaction was quenched at -78°C with ethyl acetate (20 ml), then methanol (4 ml), then slowly warmed to ambient temperature over 20 minutes under nitrogen atmosphere. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0.1% ammonium acetate in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (34 mg, 0.083 mmol, 47.7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.40 (s, 1H), 7.71 (d, J =8.8 Hz, 1H), 7.23-7.17 ( m, 2H), 7.07 (s, 1H), 4.52 (s, 2H), 4.02-3.88 (m, 3H), 3.75 (dd, J = 9.6, 5, 7 Hz, 1H), 3.42-3.26 (m, 2H), 2.05 (dcd, J = 9.9, 6.3, 2.9 Hz, 1H), 1.92-1.84 (m, 1H), 1.63 (dt, J =12.3, 3.9 Hz, 1H), 1.62-1.36 (m, 2H); MS (CIAD ^- ) m / z 409 [MH] ^- .

Example 173: 5-{7-[(1-chloro-3-hydroxypropan-2-yl)oxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione (Compound 272)

To a suspension of the product of Example 1H (0.100 g, 0.249 mmol) and cesium carbonate (0.324 g, 0.994 mmol) in dimethylformamide (1 mL) was added oxetan-3-yl-4-methylbenzenesulfonate (0.170 g, 0.746 mmol) and the resulting the mixture was heated to 60°C. After 2 hours the reaction mixture was cooled to ambient temperature, quenched with 1 M hydrochloric acid (2 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The organic layers were combined and washed with saturated aqueous ammonium chloride (4×1 ml), then 4:1 with brine and 1 M hydrochloric acid, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-( benzyloxy)-1-fluoro-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used without purification for the next reaction . MS (ESI ^- ) m/z 457 [MH] ^- .

Into a suspension of crude 5-{3-(benzyloxy)-1-fluoro-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione (0.114 g, 0.249 mmol) and pentamethylbenzene (0.074 g, 0.498 mmol) in dichloromethane (2.3 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (1.29 ml, 1 M, 1.29 mmol ) along the flask wall so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (2 ml), then anhydrous ethanol (2 ml), warmed to ambient temperature and concentrated under reduced pressure. The crude product was then dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-40% methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0231 g, 0.055 mmol, 22% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.69 (dd, J =9.1, 1.5 Hz, 1H), 7.32 (d, J =2.6 Hz, 1H), 7.19 (dd, J =9.0, 2.5 Hz, 1H), 7.03 (s, 1H), 5.12 (t, J =5.8 Hz, 1H), 4, 65 (n, J =5.1 Hz, 1H), 4.09 (s, 2H), 3.95 (dd, J =11.7, 4.0 Hz, 1H), 3.85 (dd, J =11.9, 5.5 Hz, 1H), 3.72-3.63 (m, 2H); MS (ESI ^- ) m/z 403 [MH] ^- .

Example 174 5-{1-Fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3 ^- trione (Compound 273)

Example 174A: 5-{3-(Benzyloxy)-1-fluoro-7-[(oxan-4-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3 -trione

To a solution of the product of Example 1H (120 mg, 0.298 mmol) in N,N -dimethylformamide (2 mL) was added 4-(bromomethyl)tetrahydro-2H - pyran (117 mg, 0.656 mmol) and cesium carbonate (214 mg, 0.656 mmol ). The reaction mixture was heated to 80°C for 3 hours. The reaction was then cooled to ambient temperature and partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer was further extracted with ethyl acetate (2×3 ml) and 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 residue was subjected to column chromatography (SiO ₂ , 10% methanol in dichloromethane) to give the title compound (60 mg, 0.120 mmol, 40% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (dd, J =9.0, 1.3 Hz, 1H), 7.59-7.53 (m, 2H), 7.40-7.33 (m, 2H), 7.37-7.27 (m, 2H), 7.24 (d, J =2.6 Hz, 1H), 7.20 (dd, J = 8.9, 2.5 Hz, 1H), 5.22 (s, 2H), 4.09 (s, 2H), 3.97 (d, J =6.4 Hz, 2H), 3.89 ( ddd, J =11.3, 4.4, 1.9 Hz, 2H), 2.13-1.99 (m, 1H), 1.72 (ddd, J =12.7, 4.4, 2 .1 Hz, 2H), 1.44-1.32 (m, 2H); MS (CIAD ^- ) m/z 499 [MH] ^- .

Example 174B: 5-{1-Fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3 ^- trione

Example 174A (57 mg, 0.114 mmol) and pentamethylbenzene (33.8 mg, 0.228 mmol) in a 250 mL round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (5 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.456 ml, 0.456 mmol) in dichloromethane was added dropwise over 5 minutes. After stirring for 30 minutes, the reaction was quenched at -78°C with ethyl acetate (20 ml), then methanol (4 ml), then slowly warmed to ambient temperature over 20 minutes under nitrogen atmosphere. The volatiles were removed under reduced pressure to give a solid. Heptanes (5 ml) were added, the suspension was filtered using a fritted funnel, and the collected solid was washed with additional heptanes (5 ml) to give the title compound (25 mg, 0.061 mmol, 54% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.15 (s, 1H), 7.70 (d, J =8.8 Hz, 1H), 7.22-7.15 ( m, 2H), 7.06 (s, 1H), 4.41 (s, 2H), 3.98-3.84 (m, 4H), 3.42-3.26 (m, 2H), 2 .09-2.01 (m, 1H), 1.76-1.67 (m, 2H), 1.37 (cd, J =12.1, 4.4 Hz, 2H); MS (CIAD ^- ) m/z 409 [MH] ^- .

Example 175 5-{1-Fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3 ^- trione (Compound 274)

To a suspension of the product of Example 1H (0.100 g, 0.249 mmol) and cesium carbonate (0.324 g, 746 mmol) in dimethylformamide (1 mL) was added oxetan-3-yl-4-methylbenzenesulfonate (0.113 g, 0.497 mmol) and the resulting the mixture was heated to 60°C. After 2 hours the reaction mixture was cooled to ambient temperature, quenched with 1 M hydrochloric acid (2 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The organic layers were combined and washed with saturated aqueous ammonium chloride (4×1 ml), then 4:1 with brine and 1 M hydrochloric acid, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-( benzyloxy)-1-fluoro-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used without purification for the next reaction . MS (ESI ^- ) m/z 457 [MH] ^- .

In a solution of crude 5-{3-(benzyloxy)-1-fluoro-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione (0.114 g, 0.249 mmol) in tetrahydrofuran (5 mL) wet 5% palladium on carbon (0.2 g, 0.044 mmol) was added in a 20 mL Barnstead STEM RS10 high pressure reactor. The reactor was purged with nitrogen, then filled with hydrogen gas (50 psi) and stirred for 1.4 hours at 25°C. The reactor was vented and purged with nitrogen, and the crude reaction mixture was filtered and the solid was washed with methanol (3×5 ml). The filtrate was concentrated to give a solid, which was then dissolved in dimethyl sulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-45% methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0281 g, 0.073 mmol, 29.3% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.71 (dd, J =9.0, 1.4 Hz, 1H), 7.14 (dd, J =9.0, 2 .5 Hz, 1H), 7.04 (d, J =1.3 Hz, 1H), 6.86 (d, J =2.6 Hz, 1H), 5.46-5.38 (m, 1H ), 4.99 (brt, J = 7.9 Hz, 2H), 4.59 (br dd, J = 7.7, 4.9 Hz, 2H), 4.08 (s, 2H) ; MS (ESI ^- ) m/z 367 [MH] ^- .

Example 176 5-{1-fluoro-3-hydroxy-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalen-2-yl}- 1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 275)

Example 176A: tert - butyl 4 - (6 - (benzyloxy) - 7 - (1,1 - dioxido - 4 - oxo - 1,2,5 - thiadiazolidin - 2 - yl) - 8 - fluoronaphthalene - 2 - yl) - 3,6 - dihydropyridine - 1 (2H) - carboxylate

To the product of Example 1G (400 mg, 0.860 mmol) in 1,4-dioxane (5 mL) was added tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine-1( 2H )-carboxylate (399 mg, 1.290 mmol) and sodium carbonate (1.290 ml, 2.58 mmol). Tetrakis(triphenylphosphine)palladium (0) (99 mg, 0.086 mmol) was added and the reaction mixture was sparged with N ₂ for 5 minutes. The mixture was heated at 90°C overnight. The reaction was cooled to ambient temperature and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography (SiO ₂ , dry load, 5% methanol in dichloromethane) to give the title compound (304 mg, 0.536 mmol, 62% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.88-7.70 (m, 3H), 7.59-7.55 (m, 2H), 7.40-7.28 (m, 4H), 6.36 (s, 1H), 5.26 (s, 2H), 4.11 (s, 2H), 4.08-4.03 (m, 2H), 3.59 ( t, J = 5.7 Hz, 2H), 2.63-2.54 (m, 2H), 1.44 (s, 9H); MS (CIAD ^- ) m/z 566 [MH] ^- .

Example 176B: 5-{1-fluoro-3-hydroxy-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalene-2-yl}- 1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Trifluoroacetic acid (2 ml) was added to a solution of the product of example 176A (200 mg, 0.352 mmol) in dichloromethane (2 ml). The resulting solution was stirred at ambient temperature for 30 minutes. The volatiles were removed under reduced pressure, methylene chloride (5 ml) was added and the volatiles were removed under reduced pressure (twice). The residue was subjected to the next reaction without purification. MS (APCI ⁺ ) m/z 468 [M+H] ⁺ .

To a solution of crude 5-[3-(benzyloxy)-1-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione in dichloromethane (2 ml) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (49.6 mg, 0.214 mmol) and N -ethyl- N- isopropylpropan-2-amine (27.6 mg, 0.214 mmol ). The reaction was stirred at ambient temperature for 30 minutes. The volatiles were removed under reduced pressure, methylene chloride (5 ml) was added and the volatiles were removed under reduced pressure (twice). The residue was subjected to the next reaction without purification. MS (CIAD ^- ) m / z 548 [MH] ^- .

Crude 5-{3-(benzyloxy)-1-fluoro-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalene-2-yl}- 1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione and 1,2,3,4,5-pentamethylbenzene (81 mg, 0.546 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (2 ml) was added and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1M solution of trichloroborane (64.0 mg, 0.546 mmol) in dichloromethane was added dropwise over 5 minutes. Subsequently, the reaction was quenched at -78°C with ethyl acetate (0.9 ml) and ethanol (0.1 ml), and then slowly warmed to ambient temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (4 mg, 8.71 μmol, 4.78% yield over three steps). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.22 (s, 1H), 7.80 (d, J =1.8 Hz, 1H), 7.75-7.66 ( m, 2H), 7.07 (s, 1H), 6.33 (t, J =3.7 Hz, 1H), 4.28 (s, 2H), 2.96 (s, 1H), 2, 62 (s, 2H), 2.54 (s, 4H); MS (CIAD ^- ) m / z 458 [MH] ^- .

Example 177 5-(1-Fluoro-3,7-dihydroxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 276)

To a mixture of 5-[3-(benzyloxy)-7-(cyclopropylmethoxy)-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (60 mg, 0.131 mmol) ( intermediate from the first step in the preparation of the compound of example 151) and pentamethylbenzene (97 mg, 0.657 mmol) in dichloromethane (3 ml), cooled to -78°C, a solution of BCl ₃ (0.789 ml, 0.789 mmol) in dichloromethane was added dropwise within 5 minutes. After 30 minutes the reaction was quenched with 0.5 N HCl (2 ml), diluted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was triturated with dichloromethane to give the title compound (30 mg, 0.096 mmol, 73.1% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.22 (s, 1H), 9.82 (s, 1H), 7.64 (d, J =8.6 Hz, 1H) , 7.13-7.08 (m, 2H), 7.02 (s, 1H), 4.48 (s, 2H); MS (CIAD ^- ) m / z 311.3 (MH) ^- .

Example 178 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 277)

Example 178A: 5-{3-(benzyloxy)-7-[2-(benzyloxy)ethoxy]-1-fluoronaphthalen-2-yl}-1 λ 6 ^, 2,5-thiadiazolidin-1,1,3-trione

A mixture of the compound from Example 1H (121 mg, 0.3 mmol), ((2-bromoethoxy)methyl)benzene (161 mg, 0.750 mmol) and cesium carbonate (293 mg, 0.900 mmol) in N,N -dimethylformamide (1 ml ) was stirred at 70°C for 1 hour. The mixture was cooled to ambient temperature. The solution was filtered. The filtrate was purified by flash column chromatography on silica gel (10 g), eluted with dichloromethane then dichloromethane/methanol (7:1) to give the title compound (100 mg, 0.186 mmol, 62.1% yield). MS (ESI ^- ) m/z 535 (MH) ^- .

Example 178B: 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Trichloroborane (1.36 ml, 1.36 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 5 minutes, then at 0°C for 15 minutes before quenching with ethanol (3 ml). The mixture was stirred at ambient temperature for 5 minutes and then concentrated. The resulting solid was washed with heptane (3 x 5 ml), dichloromethane (4 x 5 ml), 2% methanol in dichloromethane (2 x 5 ml) and concentrated to give the title compound (45 mg, 0.126 mmol, 74 yield .3%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.31 (br s, 1H), 7.71 (d, J =8 Hz, 1H), 7.20 (d, J = 2Hz, 1H), 7.18(dd, J =8.2Hz, 1H), 7.09(s, 1H), 4.46(s, 2H), 4.09(t, J =8Hz , 2H), 3.77 (m, 2H); MS (ESI ^- ) m/z 355 (MH) ^- .

Example 179 5-(1-Fluoro-3-hydroxy-7-propoxynaphthalene-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 278)

The title compound was prepared from the compound of Example 1H and 1-bromopropane using the methods described for Example 30 in an overall yield of 35.8%. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.18 (s, 1H), 7.73-7.67 (m, 1H), 7.18 (d, J =8.1 Hz, 2H), 7.06 (s, 1H), 4.43 (s, 2H), 4.03 (t, J =6.5 Hz, 2H), 1.78 (r, J =7.1 Hz, 2H), 1.01 (t, J =7.4 Hz, 3H); MS (CIAD ^- ) m / z 352.8 (MH) ^- .

Example 180 5-{1-Fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin-1,1,3 ^- trione (Compound 279)

The title compound was prepared from the compound of Example 1H and 2-iodopropane using the methods described for Example 30. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 10.27 (s, 1H), 7 .70 (dd, J =9.0, 1.4 Hz, 1H), 7.20 (d, J =2.6 Hz, 1H), 7.16 (dd, J =9.0, 2.5 Hz, 1H), 7.06 (s, 1H), 4.75 (n, J = 6.0 Hz, 1H), 4.47 (s, 2H), 1.32 (d, J = 6.0 Hz, 6H); MS (CIAD ^- ) m / z 352.9 (MH) ^- .

Example 181: {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetic acid (Compound 280)

In a 20 ml vented tube, glycine tert -butyl ester hydrochloride (0.144 g, 0.860 mmol), the product of Example 1G (0.2 g, 0.430 mmol), sodium tert -butoxide (0.207 g, 2.15 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl )palladium (II) (BrettPhos Pd G3 precatalyst, 12 mg, 13 µmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (BrettPhos, 7 mg, 13 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (4 ml). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 30 minutes at 100° C., the reaction mixture was cooled to ambient temperature, then quenched with 1 M hydrochloric acid (4 ml) and diluted with ethyl acetate (4 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give t -butyl {[6-(benzyloxy)-8-fluoro- 7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetate, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 514 [MH] ^- .

To a suspension of crude tert -butyl {[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino} acetate (0.222 g, 0.43 mmol) and pentamethylbenzene (0.127 g, 0.860 mmol) in dichloromethane (4.4 ml) at -78°C, a solution of boron trichloride in dichloromethane (2.58 ml, 1 M, 2, 58 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (2 ml) followed by water (2 ml), warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 4 ml), ethyl acetate (2 x 2 ml) and water (2 x 2 ml) to give the title compound (0.0388 g, 0.105 mmol, 24.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.98 (br s, 1H), 7.52 (d, J =8.9 Hz, 1H), 7.09 (dd, J = 8.9, 2.3 Hz, 1H), 6.94 (s, 1H), 6.59 (d, J = 2.3 Hz, 1H), 4.47 (s, 2H), 3, 89 (s, 2H); MS (ESI ^- ) m/z 368 [MH] ^- .

Example 182: N -(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene- 2-yl]hydroxy}acetamide (Compound 281)

To a suspension of the product of example 1H (0.200 g, 0.477 mmol) and cesium carbonate (0.466 g, 1.431 mmol) in dimethylformamide (2 ml) was added tert -butyl bromoacetate (0.155 ml, 1.05 mmol) and the resulting mixture was heated to 60°C. After 2 hours the reaction mixture was cooled to ambient temperature, quenched with 1 M hydrochloric acid (2 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The organic layers were combined and washed with saturated aqueous ammonium chloride (4×1 mL), then 4:1 brine/1M hydrochloric acid, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give t -butyl {[6 -(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetate, which was used without purification for the next reaction . MS (ESI ^- ) m/z 515 [MH] ^- .

To a solution of crude tert -butyl {[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy} acetate (0.246 g, 0.476 mmol) and pentamethylbenzene (0.141 g, 0.952 mmol) in dichloromethane (5 ml) at -78°C, a solution of boron trichloride in dichloromethane (2.86 ml, 1 M, 2.86 mmol) was slowly added along walls of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (2 ml), then anhydrous ethanol (2 ml), warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3×3 ml) to give ethyl {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene -2-yl]oxy}acetate, which was used for the next reaction without purification. MS (ESI ^- ) m/z 397 [MH] ^- .

To a solution of crude ethyl {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetate (0.190 g , 0.476 mmol) in a mixture of tetrahydrofuran (1.9 ml) and methanol (1.9 ml), 1 M aqueous sodium hydroxide (1.9 ml, 1.9 mmol) was added. After 5 minutes, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in dimethylformamide and acidified with a solution of hydrogen chloride in 1,4-dioxane (0.476 ml, 4 M, 1.0 mmol). The solution was partially concentrated under reduced pressure to give a stock solution of 2-[7-(carboxymethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-4-oxo-1λ ⁴ ,2,5-thiadiazolidin-1,1-bis (olata) in dimethylformamide, which was assigned a value of 0.053 M, taking into account a theoretical yield of 100%. MS (CIAD ^- ) m/z 369 [MH] ^- .

In a solution of 2-[7-(carboxymethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-4-oxo-1λ ⁴ ,2,5-thiadiazolidin-1,1-bis(olate) in dimethylformamide (3 ml , 0.053 M, 0.159 mmol) was added (1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate) (0.085 g, 0.223 mmol) and diethylamine (0.020 ml, 0.191 mmol) followed by N,N -diisopropyethylamine (0.111 ml, 0.636 mmol). After 5 minutes the reaction mixture was quenched with 1 M hydrochloric acid (3 ml) and diluted with ethyl acetate (3 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The organic layers were combined, washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The crude product was then dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-45% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0224 g, 0.049 mmol, 31% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.02 (s, 1H), 8.16 (t, J=5.8 Hz, 1H), 7.72 (dd, J= 9.2, 1.4 Hz, 1H), 7.25 (dd, J=9.0, 2.6 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 7, 06 (s, 1H), 4.57 (s, 2H), 4.30 (s, 2H), 3.21 (dt, J=7.6, 6.0 Hz, 2H), 1.34 (c , J=7.1 Hz, 2H), 0.72-0.60 (m, 1H), 0.41-0.32 (m, 2H), 0.07-0.08 (m, 2H); MS (ESI ^- ) m/z 436 [MH] ^- .

Example 183: N,N -diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2- yl]oxy}acetamide (Compound 282)

In a solution of {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetic acid in dimethylformamide (3 ml, 0.053 M, 0.159 mmol) from Example 182 was added (1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate) (0.085 g, 0.223 mmol) and diethylamine (0.020 ml, 0.191 mmol) followed by N,N -diisopropyethylamine (0.111 ml, 0.636 mmol). After 5 minutes the reaction mixture was quenched with 1 M hydrochloric acid (3 ml) and diluted with ethyl acetate (3 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The organic layers were combined, washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated. The crude product was then dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-45% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0123 g, 0.028 mmol, 17.5% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 7.67 (dd, J =9.1, 1.4 Hz, 1H), 7.16 (dd, J =9.0, 2 .6 Hz, 1H), 7.12 (d, J =2.6 Hz, 1H), 7.02 (s, 1H), 4.87 (s, 2H), 4.08 (s, 2H), 3.38 (k, J =7.1 Hz, 2H), 3.30 (k, J =7.1 Hz, 2H), 1.18 (t, J =7.1 Hz, 3H), 1 .04 (t, J =7.1 Hz, 3H); MS (ESI ^- ) m/z 425 [MH] ^- .

Example 184 5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione (Compound 283)

In a solution of {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetic acid in dimethylformamide (3 ml, 0.053 M, 0.159 mmol) from Example 182 was added (1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate) (0.085 g, 0.223 mmol) and pyrrolidine (0.020 ml, 0.242 mmol) followed by N,N -diisopropyethylamine (0.111 ml, 0.636 mmol). After 5 minutes the reaction mixture was quenched with 1 M hydrochloric acid (3 ml) and diluted with ethyl acetate (3 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The organic layers were combined, washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated. The crude product was then dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-45% acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0105 g, 0.024 mmol, 15.0% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.46 (s, 1H), 7.67 (d, J =8.6 Hz, 1H), 7.19-7.14 ( m, 2H), 7.03 (s, 1H), 4.82 (s, 2H), 4.08 (s, 2H), 3.51 (t, J =6.8 Hz, 2H), 3, 36-3.32 (m, 2H), 1.91 (n, J =6.8 Hz, 2H), 1.78 (n, J =6.9 Hz, 2H); MS (ESI ^- ) m/z 422 [MH] ^- .

Example 185: 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione (Compound 284)

Tri- n -butylphosphine (0.194 ml, 0.787 mmol), then 1,1'-(azodicarbonyl)dipiperidine (0.186 g, 0.739 mmol). The resulting suspension was stirred for 30 minutes and then heated to 60°C. After 24 hours, the reaction mixture was cooled to ambient temperature and additional parts of 1-(methylsulfonyl)piperidin-4-ol (0.043 g, 0.238 mmol), tri- n -butylphosphine (0.088 ml, 0.358 mmol) and 1,1'- (azodicarbonyl)dipiperidine (0.90 g, 0.358 mmol) followed by resumption of heating. After 3 days, the reaction mixture was cooled to ambient temperature, then diluted 1:1 with a mixture of acetonitrile and methanol (5 ml), then silica (2 g) was added and the mixture was concentrated under reduced pressure. The crude was loaded dry onto a 12 g Teledyne Isco gold column and purified by column chromatography with a gradient of 0-12% methanol in dichloromethane to give 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl )piperidin-4-yl]oxy}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (0.0472 g, 0.084 mmol, 33.7% yield). MS (ESI ^- ) m/z 562 [MH] ^- .

Into a suspension of 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (0.0472 g, 0.084 mmol) and pentamethylbenzene (0.025 g, 0.167 mmol) in dichloromethane (2.3 mL) a solution of boron trichloride in dichloromethane (0.840 mL, 1 M, 0.840 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (1 ml), warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 3 ml), then dissolved in dimethyl sulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-20% methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0111 g, 0.0226 mmol, 27.1% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.66 (d, J =9.0 Hz, 1H), 7.26 (d, J =2.5 Hz, 1H), 7 .17 (dd, J =9.0, 2.5 Hz, 1H), 7.02 (s, 1H), 4.68 (n, J =3.8 Hz, 1H), 4.11 (s, 2H), 3.34 (dd, J =7.4, 3.9 Hz, 2H), 3.13 (dd, J =11.9, 8.1, 3.6 Hz, 2H), 2.87 (s, 3H), 2.09-1.99 (m, 2H), 1.82-1.69 (m, 2H); MS (ESI ^- ) m/z 472 [MH] ^- .

Example 186 5-{1-Fluoro-3-hydroxy-7-[1-(oxolane-3-sulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]naphthalene-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 285)

The product from example 166 (44 mg, 0.12 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (1 ml) and pure diisopropyethylamine (63 μl, 0.36 mmol, 3.0 eq.) was added. Tetrahydrofuran-3-sulfonyl chloride (0.4 M in tetrahydrofuran, 363 μl, 0.15 mmol, 1.2 eq.) 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 5 μm Waters XBridge™ C8 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/minute (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15 -100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to give the title compounds (4.2 mg, 0.008 mmol, 7% yield). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (s, 1H), 7.72 (s, 1H), 7.08 (s, 2H), 6.58-6, 50 (m, 1H), 4.67 (td, J =4.6, 1.9 Hz, 2H), 4.38 (dt, J =6.4, 2.9 Hz, 2H), 4.26 (cd, J =7.8, 5.8 Hz, 1H), 4.09 (s, 2H), 4.02-3.92 (m, 2H), 3.85 (dt, J =8.4 , 6.6 Hz, 1H), 3.69 (dt, J =8.4, 7.0 Hz, 1H), 2.24 (k, J =7.0 Hz, 2H); MS (ESI ⁺ ) m/z 498 [M+H] ⁺ .

Example 187: 5-{1-Fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]naphthalene-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 286)

The title compound was prepared using the procedure described in Example 186, replacing 2-methoxyethane-1-sulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.74 (s, 2H), 7.70 (s, 1H), 7.08 (s, 1H), 6.49 (t, J = 2.1 Hz, 1H), 4.65-4.59 (m, 2H), 4.33 (dd, J = 5.3, 2.6 Hz, 2H), 4.09 (s, 2H ), 3.71 (t, J =5.9 Hz, 2H), 3.50 (t, J =5.9 Hz, 2H), 3.23 (s, 3H); MS (ESI ⁺ ) m/z 486 [M+H] ⁺ .

Example 188 5-{1-Fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]naphthalene- 2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 287)

The title compound was prepared using the procedure described in Example 186, replacing 3,3,3-trifluoropropane-1-sulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.93 (s, 1H), 7.75 (2, 2H), 7.71 (s, 1H), 6.51 (t, J = 2.2 Hz, 1H), 4.70 (k, J = 3.1, 1.8 Hz, 2H), 4.41-4.38 (m, 2H), 4.10 (s, 2H ), 3.55-3.48 (m, 2H), 2.82-2.68 (m, 2H); MS (ESI ⁺ ) m/z 541 [M+NH ₄ ] ⁺ .

Example 189 5-{1-fluoro-3-hydroxy-7-[1-(propane-1-sulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]naphthalene-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 288)

The title compound was prepared using the procedure described in Example 186 replacing propane-1-sulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.93 (s, 1H), 7.75 (s, 2H), 7.71 (s, 1H), 6.51 (t, J = 2.1 Hz, 1H), 4.63 (td, J = 5.1, 4.6, 1.8 Hz, 2H), 4.33 (k, J = 3.9, 3.0 Hz , 2H), 4.10 (s, 2H), 3.22-3.16 (m, 2H), 1.79-1.68 (m, 2H), 1.00 (t, J =7.4 Hz, 3H); MS (ESI ⁺ ) m/z 470 [M+H] ⁺ .

Example 190 5-(1-Fluoro-3-hydroxy-7-{1-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalene-2 - yl )-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 289)

The title compound was prepared using the procedure described in Example 186, replacing (tetrahydro- 2H -pyran-2-yl)methanesulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.74 (d, J =1.2 Hz, 2H), 7.68 (s, 1H), 7.07 (d, J = 1.2 Hz, 1H), 6.47 (t, J = 2.1 Hz, 1H), 4.63-4.57 (m, 2H), 4.30 (k, J = 2.9 Hz, 2H), 4.09 (s, 2H), 3.82-3.68 (m, 2H), 3.47 (dd, J =14.7, 8.4 Hz, 1H), 3.25 (dd , J =14.7, 3.2 Hz, 1H), 1.74 (d, J =13.1 Hz, 1H), 1.70-1.63 (m, 1H), 1.55-1, 44 (m, 1H), 1.43-1.37 (m, 2H), 1.31-1.23 (m, 2H); MS (ESI ⁺ ) m/z 526 [M+H] ⁺ .

Example 191 5-{1-Fluoro-3-hydroxy-7-[1-(4,4,4-trifluorobutan-1-sulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]naphthalene- 2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 290)

The title compound was prepared using the procedure described in Example 186, replacing 4,4,4-trifluorobutane-1-sulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.93 (s, 1H), 7.75 (s, 2H), 7.71 (s, 1H), 6.52 (t, J = 2.1 Hz, 1H), 4.67-4.61 (m, 2H), 4.35 (dd, J = 4.8, 2.6 Hz, 2H), 4.09 (s, 2H ), 2.48-2.37 (m, 2H), 1.98-1.88 (m, 2H); MS (ESI ⁺ ) m/z 538 [M+H] ⁺ .

Example 192: 5-{7-[1-(butan-1-sulfonyl)-2,5-dihydro-1 H -pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione (Compound 291)

The title compound was prepared using the procedure described in Example 186 replacing butane-1-sulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 9.93 (s, 1H), 7.75 (d, J=1.5 Hz, 2H), 7.71 (s, 1H), 7.08 (s, 1H), 6.51 (t, J =2.1 Hz, 1H), 4.66-4.60 (m, 2H), 4.35-4.31 (m, 2H), 4, 09 (s, 2H), 3.24-3.17 (m, 2H), 1.69 (tt, J = 7.8, 6.4 Hz, 2H), 1.41 (r, J = 7, 3 Hz, 2H), 1.25 (d, J =7.2 Hz, 1H), 0.90 (t, J =7.4 Hz, 3H); MS (ESI ⁺ ) m/z 484 [M+H] ⁺ .

Example 193: 5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-1H- pyrrol -3-yl}-1-fluoro-3-hydroxynaphthalene- 2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 292)

The title compound was prepared using the procedure described in Example 186 replacing (1,4-dioxan-2-yl)methanesulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.74 (s, 2H), 7.70 (s, 1H), 7.07 (s, 2H), 6.48 (t, J = 2.1 Hz, 1H), 4.65-4.60 (m, 2H), 4.33 (k, J = 5.9, 5.1 Hz, 2H), 4.09 (s, 2H ), 3.97 (t, J =8.6 Hz, 1H), 3.76 (dd, J =11.5, 2.7 Hz, 1H), 3.69-3.54 (m, 3H) , 3.49-3.41 (m, 2H), 3.30-3.25 (m, 2H); MS (ESI ⁺ ) m/z 528 [M+H] ⁺ .

Example 194 5-{3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-2 ,5-dihydro-1H- pyrrole -1-sulfonyl}pentanonitrile (Compound 293)

The title compound was prepared using the procedure described in Example 186 replacing 4-cyanobutane-1-sulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (s, 2H), 7.71 (s, 1H), 7.07 (s, 1H), 6.51 (t, J =2.1Hz, 1H), 4.63(s, 2H), 4.33(s, 2H), 4.09(d, J =1.8Hz, 2H), 3.25-3, 18 (m, 2H), 2.08 (t, J =7.2 Hz, 2H), 1.73-1.67 (m, 2H), 1.63-1.58 (m, 2H); MS (ESI ⁺ ) m/z 527 [M+NH ₄ ] ⁺ .

Example 195 5-{1-fluoro-3-hydroxy-7-[1-(pentan-2-sulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]naphthalene-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 294)

The title compound was prepared using the procedure described in Example 186 replacing pentane-2-sulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride and purified by reverse phase preparative HPLC on a 5 µm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (s, 2H), 7.70 (s, 1H), 7.07 (s, 2H), 6.55-6, 51 (m, 1H), 4.65 (s, 1H), 4.37 (s, 2H), 4.09 (s, 2H), 1.84-1.80 (m, 1H), 1.48 (s, 1H), 1.53-1.43 (m, 2H), 1.37-1.29 (m, 2H), 1.27 (d, J =6.8 Hz, 3H), 0, 90 (t, J =7.2 Hz, 3H); MS (ESI ⁺ ) m/z 498 [M+H] ⁺ .

Example 196: 5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione (Compound 295)

The title compound was prepared using the procedure described in Example 186 replacing ethanesulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (d, J=1.5 Hz, 2H), 7.71-7.70 (m, 1H), 7.08 ( d, J = 1.3 Hz, 1H), 6.51 (t, J = 2.1 Hz, 1H), 4.66-4.60 (m, 2H), 4.34 (td, J = 4 .5, 4.1, 2.3 Hz, 2H), 4.09 (s, 2H), 3.23 (k, J = 7.4 Hz, 2H), 1.25 (t, J = 7, 3 Hz, 3H); MS (ESI ⁺ ) m/z 456 [M+H] ⁺ .

Example 197 5-{1-Fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl] naphthalene -2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 296)

The title compound was prepared using the procedure described in Example 186 replacing propane-2-sulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.75 (d, J =1.6 Hz, 2H), 7.70 (d, J=1.4 Hz, 1H), 7 .08 (d, J =1.2 Hz, 1H), 6.53 (t, J =2.1 Hz, 1H), 4.66 (td, J =5.3, 4.7, 1.9 Hz, 2H), 4.38 (td, J = 4.5, 4.0, 2.2 Hz, 2H), 4.09 (s, 2H), 3.61 (hept, J = 6.8 Hz , 1H), 1.28 (s, 3H), 1.29 (s, 3H); MS (ESI ⁺ ) m/z 470 [M+H] ⁺ .

Example 198: 5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1 λ 6 ^, 2.5 -thiadiazolidin-1,1,3-trione (Compound 297)

Trifluoroacetic acid (2 ml) was added to a solution of the product of Example 176A (200 mg, 0.352 mmol) in dichloromethane (2 ml). The resulting reaction was stirred at ambient temperature for 30 minutes. The volatiles were removed under reduced pressure, methylene chloride (5 ml) was added and the volatiles were removed under reduced pressure (twice). The residue was subjected to the next reaction without purification. MS (CIAD ⁺ ) m / z 468 [M+H] ⁺ .

To a solution of crude 5-[3-(benzyloxy)-1-fluoro-7-(1,2,3,6-tetrahydropyridin-4-yl)naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione in dichloromethane (2 mL) cyclopropanesulfonyl chloride (45.1 mg, 0.321 mmol) and Hunig's base (0.187 mL, 1.069 mmol) were added. The reaction was stirred at ambient temperature for 30 minutes. The volatiles were removed under reduced pressure, methylene chloride (5 ml) was added and the volatiles were removed under reduced pressure (twice). The residue was subjected to the next reaction without purification. MS (CIAD ^- ) m / z 570 [MH] ^- .

Crude 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-fluoronaphthalen-2-yl}-1λ ^6,2,5- thiadiazolidin-1,1,3-trione (100 mg, 0.175 mmol) and 1,2,3,4,5-pentamethylbenzene (78 mg, 0.525 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, dichloromethane (2 ml) was added, and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (61.5 mg, 0.525 mmol) in dichloromethane was added dropwise over 5 minutes. Subsequently, the reaction was quenched at -78°C with ethyl acetate (0.9 ml) and ethanol (0.1 ml), and then slowly warmed to ambient temperature. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% acetonitrile gradient (A) and 0.1% ammonium acetate in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (7 mg, 0.015 mmol, 8% yield over three steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.82 (d, J =1.9 Hz, 1H), 7.72 (dd, J =8.8, 1.5 Hz, 1H), 7.70-7.59 (m, 1H), 7.06 (s, 1H), 6.41-6.34 (m, 1H), 4.09 (s, 2H), 3.98 (t, J =3.1 Hz, 2H), 3.50 (m, 2H), 2.72 (t, J =4.4 Hz, 2H), 2.71-2.62 (m, 1H) , 1.05-0.95 (m, 4H); MS (CIAD ^- ) m/z 480 [MH] ^- .

Example 199: N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy }ethyl)oxetane-3-sulfonamide (Compound 298)

To the compound from Example 210 (40 mg, 0.113 mmol) and triethylamine (46 mg, 0.45 mmol) in N,N -dimethylformamide (1 mL) was added oxetane-3-sulfonyl chloride (19.4 mg, 0.124 mmol) in N , N -dimethylformamide (0.3 ml). The mixture was stirred for 1 hour at ambient temperature and then diluted with N,N -dimethylformamide (1 ml). The mixture was filtered through a glass microfiber separator filter and the filtrate was purified by preparative HPLC [YMC TriArt™ C18 hybrid 5 µm column, 50 x 100 mm, flow rate 140 ml/min, 5-100% methanol gradient in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide)] to give the title compound (15 mg, 0.032 mmol, 28% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.53 (s, 1H), 7.69 (d, J =8 Hz, 1H), 7.20 (d, J =2 Hz , 1H), 7.18 (dd, J = 8.2 Hz, 1H), 7.11 (br s, 1H), 7.04 (s, 1H), 4.78 (m, 2H), 4 .68 (m, 3H), 4.11 (s, 2H), 4.10 (t, J = 8 Hz, 2H), 3.41 (m, 2H); MS (ESI ^- ) m/z 474 (MH) ^- .

Example 200: 5-[1-Fluoro-3-hydroxy-7-(piperidin-4-yl)naphthalen-2-yl]-1 λ 6 , ^2,5 -thiadiazolidin-1,1,3-trione (Compound 299 )

A 250 ml round bottom flask was filled with nitrogen followed by the addition of 5% Pd/C (50 mg, 0.470 mmol) and tetrahydrofuran (10 ml). Then a solution of the product of example 176A (40 mg, 0.080 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. The filtrate was concentrated under reduced pressure and the residue was taken to the next step without purification. MS (CIAD ^- ) m/z 478 [MH] ^- .

To a solution of crude tert -butyl 4-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]piperidin-1 -carboxylate in dichloromethane (2 ml) trifluoroacetic acid (2 ml) was added. The resulting mixture was stirred at ambient temperature for 30 minutes. The volatiles were removed under reduced pressure, methylene chloride (5 ml) was added and the volatiles were removed under reduced pressure (twice). The residue was then subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B ) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (24 mg, 0.063 mmol, 30% yield over two steps). ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.72 (d, J =8.5 Hz, 1H), 7.66 (d, J =1.7 Hz, 1H), 7 .38 (dd, J = 8.6, 1.8 Hz, 1H), 7.05 (s, 1H), 4.10 (s, 2H), 3.39-3.37 (m, 2H), 3.06-2.94 (m, 3H), 2.01 (dd, J =14.5, 3.6 Hz, 2H), 1.89-1.76 (m, 2H); MS (CIAD ^- ) m/z 378 [MH] ^- .

Example 201 5-{1-Fluoro-3-hydroxy-7-[1-(2-methylpropan-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl] naphthalene -2-yl} -1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 300)

5-[7-(2,5-dihydro-1 H -pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3- trione (44 mg, 0.12 mmol, 1.0 eq., example 166) was dissolved in N,N -dimethylformamide (1 ml) and pure diisopropyethylamine (63 μl, 0.36 mmol, 3.0 eq.) was added. Isobutylsulfonyl chloride (0.4 M in tetrahydrofuran, 363 μl, 0.15 mmol, 1.2 eq.) was added and the reaction was stirred overnight at ambient temperature. The reaction was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A). After purification, a number of impurities were present and the residue was redissolved in dimethyl sulfoxide/methanol and purified by reverse phase preparative HPLC on a 5 μm Waters XBridge™ C8 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 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compounds (4.0 mg, 7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.77-7.67 (m, 3H), 7.09 (s, 1H), 6.50-6.43 (m, 1H ), 4.64-4.54 (m, 2H), 4.37-4.29 (m, 2H), 4.13 (s, 3H), 3.06 (d, J = 6.6 Hz, 2H), 2.19-2.05 (m, 1H), 1.04 (d, J = 6.7 Hz, 6H); MS (ESI ⁺ ) m/z 484.3 (M+H) ⁺ .

Example 202: 5-(7-ethoxy-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 301)

The title compound was prepared from Example 1H and bromoethane in 79% yield (2-step combined yield) using the methods described for Example 12. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10 .26 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 7.06 (s, 1H), 4 .46 (s, 2H), 4.13 (k, J = 6.9 Hz, 2H), 1.38 (t, J = 6.9 Hz, 3H).

Example 203: 5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 302)

The title compound was prepared from the compound of Example 1H and 2-bromo-1,1-diphtopentane in 84% yield (2-step combined yield) using the methods described for Example 12. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.49 (s, 1H), 7.76 (d, J =9.1 Hz, 1H), 7.33 (d, J =2.6 Hz, 1H), 7, 26 (dd, J =9.0, 2.6 Hz, 1H), 7.10 (s, 1H), 6.44 (tt, J =54.5, 3.5 Hz, 1H), 4.52 (s, 2H), 4.45 (td, J =14.7, 3.5 Hz, 2H); MS (CIAD ^- ) m / z 375.2 (MH) ^- .

Example 204: 5-{7-[1-(cyclopropanesulfonyl)-1 H -pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (Compound 303)

Example 204A: 5-[3-(Benzyloxy)-1-fluoro-7-(1H-pyrazol-4-yl)naphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1,3- trion

To the product of Example 1G (120 mg, 0.258 mmol) in 1,4-dioxane (5 mL) was added tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H -pyrazole-1-carboxylate (114 mg, 0.387 mmol) and sodium carbonate (0.387 ml, 0.774 mmol). Tetrakis(triphenylphosphine)palladium (0) (29.8 mg, 0.026 mmol) was added and the reaction mixture was sparged with N ₂ for 5 minutes. The mixture was heated to 90°C for 14 hours. The reaction was cooled to ambient temperature and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography (SiO ₂ , dry load with diatomaceous earth, 5% methanol in dichloromethane) to give the title compound (63 mg, 0.139 mmol, 54% yield). MS (CIAD ^- ) m/z 451 [MH] ^- .

Example 204B: 5 - {7 - [1 - (cyclopropanesulfonyl) - 1H - pyrazol - 4 - yl] - 1 - fluoro - 3 - hydroxynaphthalene - 2 - yl} - 1 λ ⁶ ,2.5 - thiadiazolidin - 1.1 ,3 - trion

To a solution of the product of Example 204A (48 mg, 0.106 mmol) in dioxane (5 mL) was added cyclopropanesulfonyl chloride (0.022 mL, 0.212 mmol) at ambient temperature, followed by N -ethyl- N -isopropylpropan-2-amine (0.148 ml, 0.849 mmol). The reaction mixture was stirred overnight at ambient temperature. Water (5 ml) was added and the reaction was extracted with ethyl acetate (2×3 ml). The combined organic layers were mixed and dried over sodium sulfate. The volatiles were removed under reduced pressure and the residue was taken to the next step without purification. MS (CIAD ^- ) m / z 555 [MH] ^-

Crude 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)-1 H -pyrazol-4-yl]-1-fluoronaphthalen-2-yl}-1λ ⁶ ,2,5-thiadiazolidin-1,1 ,3-trione (38 mg, 0.084 mmol) and 1,2,3,4,5-pentamethylbenzene (37.4 mg, 0.252 mmol) in a 50 ml round bottom flask were purged with nitrogen for 5 minutes. After that, methylene chloride (5 ml) was added, and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.252 ml, 0.252 mmol) in dichloromethane was added dropwise over 5 minutes. Subsequently, the reaction was quenched at -78°C with ethyl acetate (0.9 ml) and ethanol (0.1 ml), and then slowly warmed to ambient temperature. Solvents were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% acetate ammonium in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (18 mg, 0.039 mmol, 37% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.92 (s, 1H), 8.63 (s, 1H), 8.26 (d, J =1.8 Hz, 1H) , 7.89 (dd, J =8.7, 1.8 Hz, 1H), 7.79 (dd, J =8.7, 1.5 Hz, 1H), 7.08 (s, 1H), 4.11 (s, 2H), 3.21-3.12 (m, 1H), 1.37-1.17 (m, 5H); MS (CIAD ^- ) m/z 465 [MH] ^- .

Example 205: 5-(1-Fluoro- 3 -hydroxy-7-{[(3 R )-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1 λ ^6.2.5 -thiadiazolidin-1,1,3-trione (Compound 304)

In a 4 ml tube were combined ( 3R )-1-methanesulfonylpyrrolidine-3-amine hydrochloride (0.086 g, 0.430 mmol), the product of Example 1G (0.1 g, 0.215 mmol), sodium tert -butoxide (0.124 g, 1.29 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-yl)palladium (II) (BrettPhos Pd G3 precatalyst, 5.8 mg, 6.5 µmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-biphenyl (BrettPhos, 3.5 mg, 6.5 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (2 ml). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 30 minutes at 100° C., the reaction mixture was cooled to ambient temperature, then quenched with 1 M hydrochloric acid (2 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-1-fluoro-7- {[(3 R )-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without cleaning. MS (CIAD ^- ) m/z 547 [MH] ^- .

To a suspension of crude 5-[3-(benzyloxy)-1-fluoro-7-{[(3 R )-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl]-1λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione (0.118 g, 0.215 mmol) and pentamethylbenzene (0.064 g, 0.430 mmol) in dichloromethane (2.4 ml) at -78°C, a solution of boron trichloride in dichloromethane (2, 15 ml, 1 M, 2.15 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (1 ml), warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 3 mL) to give a sticky solid, which was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 4-20% methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0208 g, 0.044 mmol, 20.4% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.48 (dd, J =9.0, 1.6 Hz, 1H), 6.98 (dd, J =8.9, 2 .3 Hz, 1H), 6.90 (s, 1H), 6.67 (d, J = 2.4 Hz, 1H), 4.21-4.05 (m, 1H), 4.10 (s , 2H), 3.55 (dd, J = 10.3, 5.7 Hz, 1H), 3.45-3.30 (m, 2H), 3.15 (dd, J = 10.3, 3 .7 Hz, 1H), 2.84 (s, 3H), 2.26 (dc, J =13.9, 7.5 Hz, 1H), 1.96-1.84 (m, 1H); MS (ESI ^- ) m/z 457 [MH] ^- .

Example 206: 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin- ¹ , 1,3-trione (Compound 305)

In a 4 ml tube were combined 1-(methanesulfonyl)piperidine-4-amine (0.077 g, 0.430 mmol), the product of Example 1G (0.1 g, 0.215 mmol), sodium tert -butoxide (0.062 g, 0.645 mmol), methanesulfonato( 2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (BrettPhos Pd G3 precatalyst, 5.8 mg, 6.5 µmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos , 3.5 mg, 6.5 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (2 ml). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 30 minutes at 100°C, the reaction mixture was cooled to ambient temperature, then additional parts of 1-(methanesulfonyl)piperidine-4-amine (0.077 g, 0.430 mmol), sodium tert -butoxide (0.062 g, 0.645 mmol), methanesulfonato (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (BrettPhos Pd G3 precatalyst, 5.8 mg, 6.5 µmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl ( BrettPhos, 3.5 mg, 6.5 μmol) and the reaction mixture was degassed with three cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature and then heated to 100°C. After 30 minutes at 100° C., the reaction mixture was cooled to ambient temperature, then quenched with 1 M hydrochloric acid (2 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-1-fluoro-7-{ [1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (0.121 g, 0.215 mmol) which was used for the following reaction without cleaning. MS (CIAD ^- ) m/z 561 [MH] ^- .

To a suspension of crude 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione (0.121 g, 0.215 mmol) and pentamethylbenzoa (0.064 g, 0.430 mmol) in dichloromethane (2.4 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (2.15 ml, 1 M , 2.15 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (1 ml), warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 3 mL) to give a sticky solid, which was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-20% methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0161 g, 0.033 mmol, 15.3% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.55-7.44 (m, 1H), 6.99 (dd, J =8.9, 2.3 Hz, 1H), 6.90 (s, 1H), 6.73 (d, J =2.3 Hz, 1H), 4.11 (s, 2H), 3.56-3.42 (m, 2H), 3.00 -2.90 (m, 2H), 2.88-2.84 (m, 4H), 2.10-2.01 (m, 2H), 1.51-1.38 (m, 2H); MS (ESI ^- ) m/z 471 [MH] ^- .

Example 207: 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione (Compound 306)

In a 4 ml tube were combined 1-(cyclopropylsulfonyl)pyrrolidine-3-amine (0.082 g, 0.430 mmol), the product of Example 1G (0.1 g, 0.215 mmol), sodium tert -butoxide (0.062 g, 0.645 mmol), methanesulfonate ( 2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (BrettPhos Pd G3 precatalyst, 5.8 mg, 6.5 µmol) and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos , 3.5 mg, 6.5 µmol). The solids were placed under vacuum for 5 minutes with stirring, then the tube was filled with nitrogen followed by 1,4-dioxane (2 ml). The resulting slurry was degassed with five cycles of vacuum/nitrogen backfill, stirred for 10 minutes at ambient temperature, and then heated to 100°C. After 30 minutes at 100° C., the reaction mixture was cooled to ambient temperature, then quenched with 1 M hydrochloric acid (2 ml) and diluted with ethyl acetate (2 ml). The aqueous layer was extracted with ethyl acetate (2×2 ml). The combined organic layers were washed 4:1 with brine and 1 M hydrochloric acid (1 ml), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-7-{[1- (cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, which was used for the next reaction without purification. MS (CIAD ^- ) m/z 573 [MH] ^- .

To a suspension of crude 5-[3-(benzyloxy)-7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoronaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (0.124 g, 0.215 mmol) and pentamethylbenzene (0.064 g, 0.430 mmol) in dichloromethane (2.5 ml) at -78°C was slowly added a solution of boron trichloride in dichloromethane (2.15 ml, 1 M, 2.15 mmol) along the wall of the flask so that the internal temperature remains below -70°C. The resulting solution was stirred for 5 minutes at -78°C, then the cooling bath was removed, and the reaction mixture was left to warm to an internal temperature of 0°C before cooling back to -78°C. The reaction was quenched by adding ethyl acetate (1 ml), then anhydrous ethanol (1 ml), warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3 x 3 mL) to give a sticky solid, which was dissolved in dimethylsulfoxide/methanol and filtered through a glass microfiber separator filter. The resulting solution was directly purified by preparative HPLC [5 µm column Waters XBridge™ C18 OBD, 30 x 100 mm, flow rate 40 ml/min, gradient 5-25% methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 ammonium hydroxide)] to give the title compound as the ammonium salt (0.0142 g, 0.028 mmol, 13.2% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.48 (dd, J =9.0, 1.6 Hz, 1H), 6.98 (dd, J =8.9, 2 .3 Hz, 1H), 6.90 (d, J = 1.3 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), 4.14-4.09 (m, 1H ), 4.10 (s, 2H), 3.63 (dd, J = 10.2, 5.8 Hz, 1H), 3.51-3.35 (m, 2H), 3.18 (dd, J = 10.2, 4.1 Hz, 1H), 2.69-2.57 (m, 1H), 2.28 (dt, J = 14.0, 7.0 Hz, 1H), 1.96 -1.84 (m, 1H), 1.03-0.79 (m, 4H); MS (ESI ^- ) m/z 483 [MH] ^- .

Example 208: 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5 ^- thiadiazolidine -1,1,3-trione (Compound 307)

Example 208A: 5-[3-(Benzyloxy)-1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl]-1 λ 6 ^.2 , 5-thiadiazolidin-1,1,3-trione

( E )-diazen-1,2-diylbis(piperidin-1-ylmethanone) (329 mg, 1.305 mmol). The reaction mixture was purged with N ₂ at 0° C. for 5 minutes followed by the addition of tri- n -butylphosphine (0.322 mL, 1.305 mmol). The reaction mixture was stirred at 60°C for 14 hours. After cooling to ambient temperature, the volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (34 mg, 0.058 mmol, 16% yield) . MS (CIAD ^- ) m/z 580 [MH] ^- .

Example 208B: 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1 λ 6 ,2,5 ^- thiadiazolidine -1,1,3-trione

The product from Example 208A (32 mg, 0.055 mmol) and 1,2,3,4,5-pentamethylbenzene (24.47 mg, 0.165 mmol) in a 50 mL round bottom flask were purged with nitrogen for 5 minutes. After that, methylene chloride (5 ml) was added, and the heterogeneous suspension was cooled to -78°C and equilibrated for 5 minutes. Thereafter, a 1 M solution of trichloroborane (0.165 ml, 0.165 mmol) in dichloromethane was added dropwise over 5 minutes. Subsequently, the reaction was quenched at -78°C with ethyl acetate (0.9 ml) and ethanol (0.1 ml), and then slowly warmed to ambient temperature. Solvents were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 µm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% acetate ammonium in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (12 mg, 0.026 mmol, 48%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.70 (dd, J =9.0, 1.5 Hz, 1H), 7.25 (d, J =2.6 Hz, 1H), 7.19 (dd, J =9.0, 2.5 Hz, 1H), 7.05 (d, J =1.4 Hz, 1H), 4.52-4.44 (m, 1H ), 4.44-4.34 (m, 1H), 4.11 (s, 2H), 3.68 (s, 1H), 3.67-3.48 (m, 2H), 3.46 ( td, J = 9.8, 7.5 Hz, 1H), 2.96 (s, 3H), 2.36-2.15 (m, 2H); MS (CIAD ^- ) m/z 490 [MH] ^- .

Example 209 5-{1-Fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione (Compound 308)

To a solution of the compound from Example 143A (50 mg, 0.110 mmol) in methylene chloride (5 ml) was added propane-2-sulfonyl chloride (0.025 ml, 0.221 mmol) at ambient temperature, followed by N -ethyl- N -isopropylpropane-2 -amine (0.193 ml, 1.103 mmol). The reaction mixture was stirred at ambient temperature for 5 hours. Water (5 ml) was added and the mixture was extracted with ethyl acetate (3×3 ml). The organic layers were combined, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was subjected to the next reaction without purification. MS (CIAD ^- ) m/z 558 [MH] ^- .

A 250 ml round bottom flask was filled with nitrogen followed by the addition of 5% Pd/C (25 mg, 0.235 mmol) and tetrahydrofuran (10 ml). Then a solution of crude 5-{3-(benzyloxy)-1-fluoro-7-[1-(propane-2-sulfonyl)-2,5-dihydro- 1H -pyrrol-3-yl]naphthalene-2-yl was added }-1λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione in tetrahydrofuran (2 ml). An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (5 mg, 0.01 mmol, 9.6%). ¹ H NMR (400 MHz, -d ₆ ) δ ppm 9.78 (s, 1H), 7.77 (d, J =1.6 Hz, 1H), 7.72 (dd, J =8 .6, 1.6 Hz, 1H), 7.46 (dd, J =8.7, 1.8 Hz, 1H), 7.05 (d, J =1.3 Hz, 1H), 4.11 (s, 2H), 3.81 (dd, J =9.2, 7.4 Hz, 1H), 3.65-3.42 (m, 5H), 2.41-2.29 (m, 1H ), 2.11 (dc, J =12.1, 9.0 Hz, 1H), 1.27 (d, J =6.9 Hz, 6H); MS (CIAD ^- ) m/z 470 [MH] ^- .

Example 210: 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 309)

Example 210A: 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate

To a mixture of tert -butyl (2-hydroxyethyl)carbamate (572 mg, 3.55 mmol) and triethylamine (1078 mg, 10.65 mmol) in dichloromethane (12 ml) was added methanesulfonyl chloride (427 mg, 3.73 mmol) in dichloromethane (3 ml) at 0°C. The mixture was stirred at ambient temperature for 40 minutes and then diluted with dichloromethane (50 ml). The organic phase was washed with water (20 ml) and brine (20 ml), dried over sodium sulfate and concentrated at 0°C to give the title compound (756 mg, 3.16 mmol, 89% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.92 (m, 1H), 4.29 (t, J =8 Hz, 2H), 3.48 (m, 2H), 3.04 (s, 3H), 1.45 (s, 9H).

Example 210B: tert-butyl (2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene-2- yl]oxy}ethyl)carbamate

A mixture of the compound from Example 1H, Example 210A (605 mg, 2.53 mmol) and cesium carbonate (1124 mg, 3.45 mmol) in N,N -dimethylformamide (2 ml) was stirred at 65° C. for 1 hour. The mixture was cooled to ambient temperature and diluted with ethyl acetate (50 ml). The organic phase was washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (40 g) eluted with dichloromethane followed by dichloromethane/methanol (10:1) to give the title compound (380 mg, 0.697 mmol, 60.6% yield) . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.95 (br s, 1H), 7.77 (br d, J = 8 Hz, 1H), 7.56 (br d) d, J = 8 Hz, 2H), 7.29-7.39 (m, 4H), 7.25 (d, J = 2 Hz, 1H), 7.20 (dd, J = 8. 2 Hz, 1H), 7.03(m, 1H), 5.22(s, 2H), 4.12(s, 2H), 4.10(t, J =8Hz, 2H), 3.36(m, 2H), 1.39 (s 9H); MS (ESI ^- ) m/z 544 (MH) ^- .

Example 210C: 5-[7-(2-aminoethoxy)-3-(benzyloxy)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, trifluoroacetic acid salt

A mixture of the compound from Example 210B (370 mg, 0.678 mmol) and trifluoroacetic acid (1.933 g, 16.95 mmol) in dichloromethane (2 mL) was stirred at room temperature for 20 minutes. The mixture was concentrated to give the title compound (611 mg, 0.678 mmol, 100% yield). MS (ESI ⁺ ) m/z 446 (M+H) ⁺ .

Example 210D: 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

Trichloroborane (8.12 ml, 8.12 mmol, 1 M in dichloromethane). The mixture was stirred at -78°C for 10 minutes and then at 0°C for 40 minutes. The mixture was quenched with ethanol (10 ml), stirred for 40 minutes at ambient temperature and then concentrated. The resulting solid was washed with heptane (5×10 mL), heptane/dichloromethane (1:1.5×8 mL) and concentrated to give the title compound (220 mg, 0.619 mmol, 92% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 10.37 (br s, 1H), 8.18 (br s, 3H), 7.75 (d, J =8 Hz, 1H), 7.26 (d, J =2 Hz, 1H), 7.19 (dd, J =8.2 Hz, 1H), 7.01 (s, 1H), 4.44 (s, 2H) , 4.30 (t, J = 8 Hz, 2H), 3.27 (m, 2H); MS (ESI ^- ) m/z 354 (MH) ^- .

Example 211 5-{7-[1-(1,3-dimethyl-1H- pyrazole -4-sulfonyl)-2,5-dihydro-1H - pyrrol-3-yl]-1-fluoro-3- hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 310)

The product from example 166 (44 mg, 0.12 mmol, 1.0 eq.) was dissolved in N,N -dimethylformamide (1 ml) and pure diisopropyethylamine (63 μl, 0.36 mmol, 3.0 eq.) was added. 1,3-Dimethyl-1 H -pyrazole-4-sulfonyl chloride (0.4 M in tetrahydrofuran, 363 μl, 0.15 mmol, 1.2 eq.) 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 Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) was used at a flow rate of 40 ml/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compound (6 mg, 0.0115 mmol, 10% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.36 (s, 1H), 7.79-7.69 (m, 3H), 7.12 (s, 1H), 6, 44 (t, J =2.1 Hz, 1H), 4.53 (s, 2H), 4.25 (s, 2H), 4.18 (s, 2H), 2.40 (s, 3H), 1.88 (s, 3H); MS (APCI ⁺ ) m/z 522 [M+H] ⁺ .

Example 212: N- (2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy }ethyl)ethanesulfonamide (Compound 311)

The title compound was prepared using the procedures described in Example 199 replacing ethanesulfonyl chloride with oxetane-3-sulfonyl chloride. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.55 (s, 1H), 7.69 (d, J =8 Hz, 1H), 7.35 (t, J =8 Hz , 1H), 7.20 (d, J =2 Hz, 1H), 7.16 (dd, J =8, 2 Hz, 1H), 7.04 (s, 1H), 4.13 (t, J = 8 Hz, 2H), 4.11 (s, 2H), 3.41 (m, 2H), 3.07 (k, J = 8 Hz, 2H), 1.20 (t, J = 8 Hz, 3H); MS (ESI-) m/z 446 (MH) ^- .

Example 213: 5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro-1 H- pyrrol-3-yl]-3-hydroxynaphthalene-2-yl}-1 λ ^6,2,5 -thiadiazolidin-1,1,3-trione (Compound 312)

The title compound was prepared using the procedure described in Example 211, replacing furan-3-sulfonyl chloride with 1,3-dimethyl-1 H -pyrazole-4-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 8.45-8.44 (m, 1H), 7.86 (t, J =1.8 Hz, 1H), 7.71- 7.69 (m, 3H), 7.08 (s, 1H), 6.98 (dd, J=2.0, 0.8 Hz, 1H), 6.40 (t, J =2.1 Hz , 1H), 4.57 (s, 2H), 4.27 (s, 2H), 4.15 (s, 2H); MS (CIAD ⁺ ) m/z 494 [M+H] ⁺ .

Example 214 5-{1-Fluoro-3-hydroxy-7-[1-(3-methylbutan-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl] naphthalene -2-yl} -1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 313)

The title compound was prepared using the procedure described in Example 211, replacing 3-methylbutane-1-sulfonyl chloride with 1,3-dimethyl-1 H -pyrazole-4-sulfonyl chloride. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.79 (t, J =1.5 Hz, 2H), 7.76-7.75 (m, 1H), 7.13 ( s, 1H), 6.54 (t, J = 2.2 Hz, 1H), 4.67 (d, J = 4.6 Hz, 2H), 4.38 (s, 2H), 4.18 ( s, 2H), 3.26-3.20 (m, 2H), 1.71 (dt, J=13.0, 6.6 Hz, 1H), 1.67-1.60 (m, 2H) , 0.94 (s, 3H), 0.92 (s, 3H); MS (CIAD ⁺ ) m/z 498 [M+H] ⁺ .

Example 215 5-{1-fluoro-3-hydroxy-7-[1-(thiophene-3-sulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]naphthalene-2-yl}-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 314)

The title compound was prepared using the procedure described in Example 211, replacing thiophene-3-sulfonyl chloride with 1,3-dimethyl-1 H -pyrazole-4-sulfonyl chloride. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.40 (dd, J =3.0, 1.4 Hz, 1H), 7.80 (dd, J =5.1, 3 .0 Hz, 1H), 7.74-7.70 (m, 2H), 7.56 (dd, J =5.2, 1.4 Hz, 1H), 7.11 (s, 1H), 6 .41-6.39 (m, 1H), 4.61 (s, 2H), 4.29 (d, J = 8.9 Hz, 2H), 4.18 (s, 2H), 1.20 ( s, 2H); MS (APCI ⁺ ) m/z 510 [M+H] ⁺ .

Example 216: 5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione (Compound 315)

The title compound was prepared using the procedure described in Example 211, replacing benzenesulfonyl chloride with 1,3-dimethyl-1 H -pyrazole-4-sulfonyl chloride. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.96-7.87 (m, 2H), 7.73-7.56 (m, 6H), 7.05 (s, 1H ), 6.37-6.32 (m, 1H), 4.55 (d, J = 4.4 Hz, 2H), 4.24 (d, J = 8.7 Hz, 2H), 4.13 (s, 2H); MS (APCI ⁺ ) m/z 504 [M+H] ⁺ .

Example 217: 5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1H- pyrrol -3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ .2, 5-thiadiazolidin-1,1,3-trione (Compound 316)

5-[7-(2,5-dihydro- 1H -pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ⁶ ,2,5-thiadiazolidin-1 ,1,3-trione (38 mg, 0.105 mmol, Example 166) in N,N -dimethylformamide (1 mL). Pure N -ethyl- N -isopropylpropan-2-amine (0.055 ml, 0.314 mmol) was added followed by cyclobutanesulfonyl chloride (0.288 ml, 0.115 mmol, 0.4 M in tetrahydrofuran). The reaction was stirred overnight at ambient temperature. The reaction was purified by reverse phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (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/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give the title compound (32 .5 mg, 64% yield. ¹ H NMR (501 MHz, DMSO- d ₆ ) δ ppm 7.74 (s, 2H), 7.70 (s, 1H), 7.10 (s, 1H), 6.50 (t, J = 2.2 Hz, 1H), 4.61-4.55 (m, 2H), 4.35-4.29 (m, 2H), 4.28-4.18 (m, 1H), 4 .15 (s, 2H), 2.50-2.37 (m, 2H), 2.29-2.19 (m, 2H), 2.07-1.86 (m, 2H); MS (ESI ⁺ ) m/z 481.9 (M+H) ⁺ .

Example 218: methyl (2 S )-2-amino-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl) naphthalen-2-yl]oxy}butanoate (Compound 317)

Example 218A: methyl (2S)-4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene-2 -yl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate

To a solution of the compound from Example 1H (120 mg, 0.298 mmol) in N,N -dimethylformamide (2 mL) was added cesium carbonate (214 mg, 0.656 mmol) and methyl ( 2S )-4-bromo-2-[( tert -butoxycarbonyl)amino]butanoate (177 mg, 0.596 mmol). The mixture was heated to 80° C. overnight. After cooling to ambient temperature, the volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes at a flow rate of 25 ml/minute] to give the title compound (120 mg, 0.194 mmol, 65% yield) . MS (CIAD ^- ) m/z 616 [MH] ^- .

Example 218B: methyl (2S)-2-amino-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ 6 ^, 2,5-thiadiazolidin-2-yl)naphthalene -2-yl]hydroxy}butanoate

A 250 ml round bottom flask was filled with nitrogen followed by the addition of 5% Pd/C (18 mg, 0.166 mmol) and tetrahydrofuran (8 ml). Then a solution of the compound from example 218A (100 mg, 0.166 mmol) in tetrahydrofuran (2 ml) was added. An adapter equipped with a hydrogen balloon was inserted and the flask was emptied and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a bed of diatomaceous earth under nitrogen gas. The volatiles were removed under reduced pressure and the crude material was carried to the next step without purification. MS (CIAD ^- ) m/z 526 [MH] ^- .

Into a solution of crude methyl (2 S )-2-[( tert -butoxycarbonyl)amino]-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo- ^1λ 6,2,5- thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanoate (50 mg, 0.95 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml). The resulting reaction mixture was stirred at ambient temperature for 30 minutes. Volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm), 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) for 15 minutes at a flow rate of 25 ml/minute] to give the title compound (31 mg, 0.057 mmol, 60% yield). ¹ H NMR (600 MHz, DMSO- d ₆ ) δ ppm 9.56 (s, 1H), 8.44 (s, 3H), 7.69 (dd, J= 9.2, 1.3 Hz, 1H), 7.19 (d, J= 2.6 Hz, 1H), 7.11 (dd, J =9.0, 2.6 Hz, 1H), 7.04 (s, 1H), 4.29 (t, J =6.1 Hz, 1H), 4.26-4.20 (m, 2H), 4.11 (s, 2H), 3.79 (s, 3H), 2.37 -2.29 (m, 2H); MS (CIAD ⁺ ) m/z 428 [M+H] ⁺ .

Example 219 5-{7-[(3,5-dimethyl-1H- pyrazol -4-yl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1 λ ⁶ ,2,5-thiadiazolidine -1,1,3-trione (Compound 318)

The title compound was prepared using the procedures described in Example 34 with tert -butyl 4-(hydroxymethyl)-3,5-dimethyl- 1H -pyrazole-1-carboxylate replaced with tert -butyl 4-(hydroxymethyl)- 1 H -pyrazole-1-carboxylate. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 10.08 (br s, 1H), 7.66 (dd, J=8, 2 Hz, 1H), 7.33 (d, J=2Hz, 1H), 7.16(dd, J=8, 2Hz, 1H), 7.10(m, 1H), 7.06(s, 1H), 5.10(s, 2H) , 4.39 (s, 2H), 2.22 (s, 6H); MS (ESI ^- ) m/z 419 (MH) ^- .

Example 220: 5-[7-(3,5-dimethyl-1 H -pyrazol-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1, 1,3-trione (Compound 319)

Example 220A: 5-[3-(Benzyloxy)-7-(3,5-dimethyl-1H-pyrazol-4-yl)-1-fluoronaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1 ,1,3-trione

To a microwave tube was added the product of Example 1G (0.200 g, 0.430 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (0.053 g, 0.064 mmol), tert -butyl 3, 5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H - pyrazole-1-carboxylate (0.277 g, 0.860 mmol) and potassium carbonate (0.178 g, 1.29 mmol). The flask was sealed, emptied and refilled with nitrogen. The empty/refill cycle was further repeated three times. Thereafter, a mixture of dimethylacetamide (1.9 ml) and water (0.24 ml) was added, degassed by the empty/refill process described above. Then the tube was heated to 85°C for 14 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate (15 ml) and 0.1 M hydrochloric acid (25 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×10 ml). The organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was loaded onto diatomaceous earth and purified by silica gel chromatography (24 g column, 0 to 30% methanol in dichloromethane) to give the title compound (0.077 g, 0.16 mmol, 37% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.92 (d, J =8.5 Hz, 1H), 7.80 (d, J =1.6 Hz, 1H), 7 .61-7.51 (m, 3H), 7.47 (s, 1H), 7.39 (t, J = 7.3 Hz, 2H), 7.33 (dd, J = 8.4, 6 .0 Hz, 1H), 5.29 (s, 2H), 4.46 (s, 2H), 2.27 (s, 6H); MS (CIAD ⁺ ) m/z 481.3 [M+H] ⁺ .

Example 220B: 5-[7-(3,5-dimethyl-1H-pyrazol-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ 6 ,2,5-thiadiazolidin ^- 1,1 ,3-trione, ammonium salt

The product from Example 220A (0.067 g, 0.14 mmol) was suspended in tetrahydrofuran (4 ml) and added to a 20 ml Barnstead Hast C reactor containing 10% palladium hydroxide on carbon (0.067 g, 0.24 mmol). The resulting mixture was stirred at ambient temperature for 24 hours under a hydrogen atmosphere (65 psi). The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was loaded onto diatomaceous earth and purified by reverse phase chromatography (30 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 dry ice] ) to give the title compound (0.022 g, 0.054 mmol, 39% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.33 (br s, 1H), 9.77 (s, 1H), 7.76 (dd, J =8.6, 1 .5 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.43 (dd, J = 8.6, 1.7 Hz, 1H), 7.12 (br. s , 3H), 7.08 (s, 1H), 4.11 (s, 2H), 2.23 (s, 6H); MS (CIAD ⁺ ) m/z 391.4 [M+H] ⁺ .

Example 221 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione (Compound 320)

Example 221A: 5-[3-(Benzyloxy)-7-(2-cyclohexylethoxy)-1-fluoronaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione

The product of example 1H (0.150 g, 0.373 mmol), (2-bromoethyl)cyclohexane (0.142 g, 0.746 mmol), cesium carbonate (0.364 g, 1.12 mmol) and N,N -dimethylformamide (1.5 ml ). The resulting mixture was stirred at ambient temperature. After 13 hours 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 (2×10 ml). The organic layers were combined and washed with saturated aqueous ammonium chloride (3×15 ml). The ammonium chloride wash was 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 to give the title compound, which was used in the next reaction without additional cleaning. MS (CIAD ⁺ ) m/z 513.4 [M+H] ⁺ .

Example 221B: 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1 λ ⁶ ,2,5-thiadiazolidin-1,1,3-trione, ammonium salt

A tube containing the product of Example 221A and 1,2,3,4,5-pentamethylbenzene (0.111 g, 0.746 mmol) in dichloromethane (3.7 ml) was cooled to -78°C with stirring under nitrogen atmosphere. Thereafter, trichloroborane (1.0 M in dichloromethane) (2.24 ml, 2.24 mmol) was slowly added along the wall of the tube. The resulting mixture was stirred at -78° C. for 10 minutes and then the dry ice/acetone bath was changed to an ice/water bath. After 10 minutes the mixture was re-cooled to -78°C and extinguished with ethyl acetate (2 ml) and then ethanol (2 ml). The mixture was then allowed to warm to ambient temperature and stirred for 15 minutes. The mixture was concentrated under reduced pressure and the residue was treated with ethanol (2×5 ml) and concentrated. The residue was dissolved in methanol, loaded onto diatomaceous earth, concentrated under reduced pressure and purified by reverse phase chromatography (30 g Biotage® Sfär C18 Duo 100 Å 30 µm column, 10 to 100% methanol in water [buffered with 0.025 M aqueous bicarbonate ammonium, adjusted to pH 7 with dry ice]) to give the title compound as the ammonium salt (0.055 g, 0.13 mmol, 34% yield over two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.42 (br s, 1H), 7.65 (dd, J =9.0, 1.6 Hz, 1H), 7, 17 (d, J = 2.6 Hz, 1H), 7.11 (dd, J = 9.0, 2.5 Hz, 1H), 7.09 (br s, 3H), 7.02 (s , 1H), 4.11-4.08 (m, 2H), 4.10 (s, 2H), 1.81-1.72 (m, 2H), 1.71-1.57 (m, 5H ), 1.57-1.43 (m, 1H), 1.29-1.11 (m, 3H), 0.97 (cd, J =12.1, 3.2 Hz, 2H); MS (CIAD ^- ) m/z 421.3 [MH] ^- .

Example 222: 2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-1 H -imidazole -4-carbonitrile (Compound 321)

Example 222A: 2-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1 λ ⁶ ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]-1- {[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-carbonitrile

To a microwave tube was added the product of Example 126A (0.150 g, 0.293 mmol), 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl) -1H- imidazole-4-carbonitrile (0.177 g, 0.586 mmol) , potassium carbonate (0.121 g, 0.878 mmol) and [(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2′-amino-1, 1'-biphenyl)]palladium(II) methanesulfonate (0.019 g, 0.029 mmol). The flask was sealed, emptied and refilled with nitrogen. The empty/refill cycle was further repeated three times. Thereafter, 1,4-dioxane (1.2 ml) and water (0.29 ml) were added, degassed by the empty/refill process described above. Then the tube was heated to 125°C for 2 hours. The tube was cooled to ambient temperature. After that was added acetonitrile (4 ml) and then 1 M hydrochloric acid (12 ml). The resulting mixture was stirred for 5 minutes and the precipitate was collected by filtration. The solid was washed with acetonitrile (4 mL) and ethyl acetate (4 mL), then dried in vacuo to give the title compound (0.155 g, 0.255 mmol, 87% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.54 (s, 1H), 8.48 (d, J =1.6 Hz, 1H), 8.04-7.98 ( m, 2H), 7.58-7.51 (m, 3H), 7.42-7.37 (m, 2H), 7.37-7.31 (m, 1H), 5.49 (s, 2H), 5.32 (s, 2H), 4.50 (s, 2H), 3.69-3.60 (m, 2H), 1.01-0.82 (m, 2H), -0, 04 (s, 9H); MS (CIAD ⁺ ) m/z 608.4 [M+H] ⁺ .

Example 222B: 2-(7-(1,1-Dioxydo-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl)-1H-imidazol-4 -carbonitrile, ammonium salt

A flask containing a suspension of the product of Example 222A (0.144 g, 0.237 mmol) and 1,2,3,4,5-pentamethylbenzene (0.105 g, 0.711 mmol) in dichloromethane (2.4 ml) was cooled to -78°C with stirring in a nitrogen atmosphere. Thereafter, trichloroborane (1.0 M in dichloromethane) (2.13 ml, 2.13 mmol) was slowly added along the wall of the flask. The resulting mixture was stirred at -78° C. for 10 minutes and then the dry ice/acetone bath was changed to an ice/water bath. After 10 minutes, the mixture was re-cooled to -78°C and extinguished with ethyl acetate (3 ml) and then ethanol (3 ml). The mixture was then allowed to warm to ambient temperature and stirred for 15 minutes. The mixture was concentrated under reduced pressure and the residue was then treated with ethanol (2×5 ml) and concentrated. The residue was dissolved in methanol, loaded onto diatomaceous earth, concentrated under reduced pressure and purified by reverse phase chromatography (100 g Isco Redi Sep Rf Gold C18 column, 5 to 75% methanol in water [buffered with 0.025 M aqueous ammonium bicarbonate adjusted to pH 7 with carbon dioxide]) to give the title compound (0.053 g, 0.13 mmol, 55% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 13.60 (s, 1H), 10.12 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J = 8.7, 1.8 Hz, 1H), 7.85 (dd, J = 8.8, 1.5 Hz, 1H), 7.15 (bt , J = 50.3 Hz, 4H), 7.12 (s, 1H), 4.12 (s, 2H); MS (CIAD ⁺ ) m/z 388.3 [M+H] ⁺ .

Biological research

Abbreviations

BSA - bovine serum albumin; DMEM - medium Needle in Dulbecco's modification; DMSO - dimethyl sulfoxide; DTT - dithiothreitol; D5W - 5% dextrose in water; EDTA - ethylenediaminetetraacetic acid; EGTA - ethylene glycol-bis (2-aminoethyl ether) - N, N, N', N' -tetraacetic acid; FBS - fetal bovine serum; GEPES - 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; IFN γ - interferon gamma; FSB - phosphate-saline buffer solution; PEG-400 - polyethylene glycol 400; RPMI 1640 - Wednesday 1640 Roswell Park Cancer Institute; S-MEM - minimal culture medium Needle, Spinner's modification; TNFα - tumor necrosis factor alpha; and Twin ® 20 - polyethylene glycol sorbitan monolaurate.

Example 223 Mobility Shift Assay to Determine the Activity of PTPN2 Inhibitors

Compound activity was determined using the in vitro 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 carried out 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 applied to a white 384-well ProxiPlate™ plate (PerkinElmer, cat# 6008289) using different concentrations of Labcyte Echo (12 points, 1:3 dilution). Enzyme (at 0.5 nM) was incubated with compound for 10 minutes at room temperature. Substrate was then added to the plates (probe sequence based on phosphorylated insulin receptor: ((OG488)-(NH-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O-CH ₂ -CO)-TRDI-(PY)- ETDYYRKK-NH ₂ ) (SEQ ID NO: 2) at a concentration of 2 μM and incubated for another 10 minutes at room temperature Finally, quench solution (water and 4-bromo-3-(2-oxo-2 -propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid), after which they were read on the EZ Reader device (excitation at 488 nm, emission at 530 nm) to measure % conversion (amount of phosphorylated substrate that was dephosphorylated by 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) were used to calculate the % inhibition After that, the % inhibition was used to calculate the IC ₅₀ values.

Example 224 Mobility Shift Assay (MSA) to determine the activity of PTP1B inhibitors

Compound activity was determined using the in vitro His-tagged full-length PTP1B protein (SEQ ID NO: 3) in an in vitro enzymatic reaction. The enzymatic assay used to determine activity is a mobility shift assay using the LabChip EZ Reader from Caliper Life Sciences. The enzymatic reaction was carried out 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 applied to a white 384-well ProxiPlate™ plate (PerkinElmer, cat ^# 6008289) using different concentrations (12 points, 1:3 dilution) and a Labcyte Echo® fluid manipulator. Enzyme (at 0.5 nM) was incubated with compound for 10 minutes at room temperature. Substrate was then added to the plates (probe sequence based on phosphorylated insulin receptor: ((OG488)-(NH-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O-CH ₂ -CO)-TRDI-(PY)- ETDYYRKK-NH ₂ ) (SEQ ID NO: 2) at a concentration of 2 μM and incubated for another 10 minutes at room temperature Finally, quench solution (water and 4-bromo-3-(2-oxo-2 -propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid), after which they were read on the EZ Reader device (excitation at 488 nm, emission at 530 nm) to measure % conversion (amount of phosphorylated substrate that was dephosphorylated by PTP1B) 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) were used to calculate the % inhibition After that, the % inhibition was used to calculate the IC ₅₀ values.

Table 2 below summarizes the IC ₅₀ data obtained using the PTPN2 ASP analysis and the PTP1B ASP analysis for exemplary compounds of the invention. In this table, "A" represents an IC ₅₀ less than 1 nM; "B" - IC ₅₀ from 1 nM to 10 nM; "C" - IC ₅₀ more than 10 nM and up to 100 nM; and "D" - IC ₅₀ more than 100 nm.

Table 2 : IC ₅₀ values of exemplary compounds of the invention in a mobility shift assay (MSA) of PTPN2 and PTP1B.

Connection No. PTPN2 ASP IC ₅₀ (nM) PTP1B ASP IC ₅₀ (nM) Connection No. PTPN2 ASP IC ₅₀ (nM) PTP1B ASP IC ₅₀ (nM) 100 B C 212 B B 101 A B 213 A B 102 B C 214 B B 103 B C 215 B B 104 B C 216 B B 105 B B 217 B B 106 B B 218 B B 107 C D 219 B C 108 B B 220 C D 109 B C 221 C D 110 B C 222 D C 111 A B 223 B B 112 C C 224 B B 113 A A 225 C 114 B B 226 B C 115 A B 227 B D 116 B C 228 B C 117 B B 229 C C 118 B B 230 B D 119 B B 231A B 120 A A 231B B B 121 B B 232 B C 122 C C 233 B C 123 B B 234 C C 124 B B 235 B A 125 B C 236 B D 126 B B 237 B A 127 A B 238 C D 128 B B 239 B C 129 A A 240 B B 130 A B 241 D D 131 B C 242 B B 132 A A 243 C D 133 B B 244 C 134 D 245 B B 135 B C 246 B D 136 B C 247 B B 137 B B 248 B D 138 B C 249 B D 139 B C 250 B B 140 B C 251 B 141 A B 252 B B 142 B C 253 B 143 B C 254 B D 144 B C 255 B D 145 C C 256 A B 146 B B 257 B C 147 A B 258 B C 148 B D 259 B B 149 B B 260 B C 150 B B 261 B B 151 B B 262 B C 152 B B 263 A D 153 B B 264 B C 154 A B 265 B B 155 A B 266 B D 156 A B 267 C C 157 B C 268 B C 158 B B 269 B B 159 A B 270 B B 160 B B 271 A D 161 C C 272 B C 162 B C 273 B D 163 A D 274 B B 164 A D 275 B C 165 B B 276 B D 166 B D 277 B D 167 C D 278 B C 168 A B 279 B D 169 B C 280 C D 170 A B 281 B C 171 A C 282 B C 172 B D 283 B C 173 A C 284 B B 174 B D 285 A B 175 C C 286 A A 176 B B 287 A B 177 B D 288 A A 178 B C 289 A A 179 C D 290 A A 180 B C 291 A A 181 B B 292 A A 182 A A 293 A A 183 B B 294 A A 184 A B 295 A A 185 B C 296 A A 186 B C 297 B B 187 B C 298 A A 188 B B 299 B C 189 B C 300 A A 190 B 301 B D 191 B 302 B C 192 A A 303 A B 193 A C 304 B C 194 A B 305 C D 195 A B 306 B C 196 B 307 B B 197 B D 308 A B 198 B C 309 B 199 B D 310 A B 200 B A 311 A B 201 B B 312 A A 202 B C 313 A A 203 B D 314 A A 204 A A 315 A A 205 C C 316 A A 206 B B 317 B 207 B B 318 B 208 B D 319 B 209 B C 320 A 210 A B 321 B 211 A A

Example 225: IFN γ Inhibition Assay on B16F10 Cell Growth Inhibition

B16F10 murine melanoma cells (ATCC, cat. ^no . CRL-6475, Manassas, VA) were plated at a density of 500 cells per well in a 384-well clear bottom plate (Corning, cat. ^no . 3765, Corning, NY) in a total volume of 25 μl DMEM+10% FBS (Sigma cat. ^no . D6429 and Sigma Cat cat. ^no . F4135, St. Louis, MO). Cells were left to attach overnight at 37°C+5% CO ₂ . The next day, 12.5 μl of mouse IFNγ (RD systems, catalog ^# 485-MI/CF, Minneapolis, MN) at a concentration of 2 ng/ml was added to half the plate (wells 13-24) to a final analytical concentration of 0.5 ng /ml IFNγ. Only medium (12.5 μl DMEM+10% FBS) was added to the remainder of the plate (wells 1-12). Thereafter, compounds resuspended in DMSO (Sigma, catalog ^# D2650) at 100 mM were diluted in semi-log dilutions of DMSO ranging from 100 mM to 0.001 mM, and DMSO-only controls were also 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 in both treatment groups (with and without IFNγ). Final concentrations ranged from 100 μM to 0.001 μM with a final DMSO concentration of 0.1%. Compounds were dosed only into the inner 240 wells, leaving the outer 2-well perimeter intact to minimize edge effects. Finally, the plates were loaded into an IncuCyte® S3 live cell assay system (Essen Bioscience-Sartorius, Ann Arbor, MI) that was in an incubator at 37°C+5% CO ₂ , allowed to equilibrate for 2 hours, and imaged every 6 hours within 5 days. Confluence was measured over time for compound dilutions in the presence or absence of IFNγ. Growth inhibition values were obtained when the DMSO/no IFNγ control reached >95% confluence. At these time points, the percentage of growth inhibition for each compound at the indicated concentration was calculated relative to the "DMSO/c IFNγ" control.

The search for new strategies to inhibit tumor growth is an active field of research in the development of oncological drugs. The growth of certain types of cancer can be suppressed by IFNγ, a cytokine produced by immune system cells such as T cells or NK cells. Ablation of IFNγ signaling promotes tumor growth. In contrast, an increase in IFNγ signaling enhances the inhibition of tumor growth. Thus, since PTPN2 is a negative regulator of IFNγ signaling, an active inhibitor of PTPN2 should help stop tumor growth in the presence of IFNγ.

The compounds of the present invention enhance the inhibition of B16F10 melanoma growth in the presence of IFNγ. Tumor growth inhibition in Table 3 is expressed as % compound inhibition relative to DMSO control. Importantly, tumor growth inhibition is not observed in the absence of IFNγ, indicating a target-directed mechanism for the compounds.

Table 3 below summarizes the percent growth inhibition data obtained from the B16F10 growth inhibition assay with and without IFNγ for exemplary compounds of the invention. In this table, "A" represents the percentage of growth inhibition > 90%; "B" - the percentage of growth inhibition 60-90%; "C" - the percentage of growth inhibition 25-59%; and "D" is the percentage of growth inhibition <25%.

Table 3 : Percent growth inhibition values of exemplary compounds of the invention in the B16F10 growth inhibition assay.

Connection No. % growth inhibition B16F10 (+ 0.5 ng/ml IFNγ)
at 33 µM % B16F10 growth inhibition (without IFNγ)
at 33 µM 100 A D 101 B D 102 B D 103 B D 104 C D 105 B D 106 B D 107 B D 108 C D 109 D D 110 B D 111 B D 112 C D 113 A D 114 B D 115 B D 116 A D 117 C D 118 B D 119 B D 120 B D 121 B D 122 B D 123 B D 124 B D 125 B D 126 B D 127 B D 128 A D 129 A D 130 B D 131 A D 132 B D 141 B D 147 A D 150 A D 154 B D 155 B B 156 B D 157 B D 158 B D 159 A D 163 A D 164 A D 165 A D 166 A D 167 B D 168 A D 169 A D 170 B D 174 A D 176 A D 177 A D 178 B D 179 A D 180 B D 181 B D 182 B D 184 C D 192 B D 193 C D 195 B D 198 B D 200 A D 201 B D 203 B D 204 B D 205 C D 206 B D 207 C D 208 D D 209 B D 210 A D 211 B D 212 B D 213 B D 214 B D 215 B D 216 C D 217 C D 218 C D 223 B D 224 A D 226 B D 227 B D 235 B D 237 A D 238 D D 239 B D 240 C D 242 B D 243 C D 245 B D 246 B D 247 B D 248 B D 249 B D 250 B D 252 C D 254 B D 255 B D 256 C D 257 C D 259 D D 260 C D 261 C D 263 B D 264 B D 271 B D 273 B D 274 B D 276 C D 277 B D 278 B D 279 B D 281 C D 282 C D 283 C D 295 A D 296 A D 297 C D 298 A D 299 A D 300 B D 301 B D 302 B D 303 B D 304 A D 305 B D 306 B D 307 C D 309 B D 310 A D 311 B D 313 B D

Table 4 : Comparison of IC ₅₀ values of compound 124 and compound X

Compound X

in the PTPN2 mobility shift assay (MSA) and percent growth inhibition values of exemplary compounds of the invention in the B16F10 growth inhibition assay.

Connection No. PTPN2 ASP IC ₅₀ (nM) % growth inhibition of B16F10 (+ 0.5 ng/ml IFNγ) at 33 µM % growth inhibition of B16F10 (without IFNγ) at 33 μM 124 B B D x ^* C D D

^* PTP1B activity of compound X (Na salt) according to the literature is from 5 to 300 nM (International patent publication WO2008148744A1)

In the case of IC ₅₀ data from PTPN2 ASP analysis, "A" represents an IC ₅₀ of less than 1 nM; "B" - IC ₅₀ from 1 nM to 10 nM; "C" - IC ₅₀ more than 10 nM and up to 100 nM; and "D" - IC ₅₀ more than 100 nm. Percent growth inhibition data obtained from B16F10 growth inhibition assay with and without IFNγ for exemplary compounds of the invention. In this table, "A" represents the percentage of growth inhibition >90%;"B" - the percentage of growth inhibition 60-90%; "C" - the percentage of growth inhibition 25-59%; and "D" - percentage of growth inhibition < 25%.

Table 4 compares literature-known compound X and compound 124. According to the literature, compound X showed a biochemical IC ₅₀ of 5 to 300 nM at PTP1B. The PTPN2 IC ₅₀ of compound X was found to be 69 nM, while compound 124 showed an IC ₅₀ at PTPN2 of 4.4 nM. At 33 μM in the IFNγ-induced growth inhibition of B16F10 cells described above, Compound 124 showed 60-90% growth inhibition, while Compound X showed <25% growth inhibition in the presence of IFNγ compared to DMSO control. These data demonstrate a significant increase in both biochemical and cellular activity of the fluoronaphthyl compound 124 compared to the corresponding desfluoronaphthyl compound X. The activity of compound 124 is IFNγ dependent, as demonstrated by the absence of observed growth inhibition in the absence of IFNγ.

Example 226: T Cell Activation and Function Assay

Pan T cells were isolated from C57BL6 splenocytes using the MACS II pan T cell isolation kit (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 medium supplemented with 10% PBS, 50 nM 2-mercaptoethanol, 100 U/ml penicillin, and 100 μg/ml streptomycin and incubated with the indicated concentration of the compound or DMSO in duplicate. After 1 hour, mouse CD3/CD28 T cell activator Dynabeads (ThermoFisher Scientific, Waltham, MA) was added at a ratio of 1:5 beads to cells to stimulate T cells for 2 or 3 days as indicated below. T cells with or without compound were incubated in the absence of T cell activator beads (medium only) as a control.

After 2 days of stimulation, the activation status of T cells was assessed by flow cytometry. T cells were exposed to fixed viability dye Zombie Violet™ (BioLegend, San Diego, CA) to exclude dead cells, washed, and then stained with BUV805-labeled anti-CD8, APC-R700-labeled anti-CD25 (both from BD Biosciences, San Jose, CA) and PE-labeled anti-CD69 (BioLegend, San Diego, CA) antibodies. After staining, cells were fixed with 2% paraformaldehyde and data were acquired on a BD LSRFortessa™ X-20 flow cytometer (BD Biosciences, San Jose, CA) using BD FACSDiva™ software. Data was analyzed using FlowJo V10 (Flow Jo LLC, Ashland, OR). Dead cells were excluded and the frequencies of activated CD8 T cells were presented as the frequencies of CD25+ or CD69+ cells in the CD8+ population. The level of expression of CD25 and CD69 indicates the activation status of the cells per cell and was assessed by the mean fluorescence intensity (MFI) of CD25 and CD69.

After 3 days of stimulation, supernatants were collected and IFNγ and TNFα in the supernatants were assessed using MSD V-plex analysis (Meso Scale Discovery, Rockville, MD).

Increasing T-cell activation and, most importantly, T-cell function is the main strategy of immune approaches in oncology aimed at stimulating antitumor immunity. An in vitro assay using primary T cells is commonly used to evaluate the effect of a compound on T cell activation and function.

Expression of CD25 (IL2 receptor alpha chain) and CD69 (very early antigen) on T cells after TCR (T cell receptor) stimulation is indicative of T cell activation, which can be analyzed, for example, by flow cytometry. The immunostimulatory compound is expected to increase the frequency of CD25 and CD69 expressing T cells and potentially increase the expression level of CD25 and CD69 per cell expressed as CIF.

An outcome of T cell function important for antitumor immunity is the production of proinflammatory, antitumorogenic cytokines such as IFNγ and TNFα. It can be assessed by detecting cytokines in in vitro supernatants of stimulated T cells. The immunostimulatory compound is expected to increase the production of IFNγ and TNFα.

Typical compounds - compound 124, compound 113, compound 182 and compound 260 - increased both T cell activation and T cell function (Table 5). Importantly, none of the compounds activated T cells in the absence of TCR stimulation, indicating that these compounds may promote the activity and function of activated T cells (such as tumor-specific T cells), but do not promote non-specific T cell activation. cells (i.e., naive T cells).

In Tables 5-A, 5-B, 5-C and 5-D : Flow cytometry data from T cell activation and function analysis. (All values are replicate averages.)

Table 5-A Compound 113 (µM) without TKR stimulation Mouse anti-CD3/anti-CD28 T-cell activator Dynabeads
(1:5 granules:cells) CIF CD25 0 48.85 373 thirty 51.7 1265 CIF CD69 0 31.75 436 thirty 28.8 1891 % CD25 to CD8+ 0 0.43% 16.20% thirty 0.49% 44.55% % CD69 to CD8+ 0 0.25% 24.05% thirty 0.24% 73.95% Table 5-B Compound 124 (µM) without TKR stimulation Mouse anti-CD3/anti-CD28 T-cell activator Dynabeads
(1:5 granules:cells) CIF CD25 0 54 363 thirty 57.05 846.5 CIF CD69 0 32.65 460.5 thirty 28.1 1421.5 % CD25 to CD8+ 0 0.34% 16.00% thirty 0.39% 32.55% % CD69 to CD8+ 0 0.22% 25.70% thirty 0.23% 61.90%

Table 5-C Compound 182 (µM) without TKR stimulation Mouse anti-CD3/anti-CD28 T-cell activator Dynabeads
(1:5 granules:cells) CIF CD25 0 46.9 262 thirty 72.4 741 CIF CD69 0 16.5 486.5 thirty 18.3 1601.5 % CD25 to CD8+ 0 0.36% 10% thirty 1.17% 29.20% % CD69 to CD8+ 0 0.80% 22.90% thirty 0.45% 61.90% Table 5-D Compound 260 (µM) without TKR stimulation Mouse anti-CD3/anti-CD28 T-cell activator Dynabeads
(1:5 granules:cells) CIF CD25 0 26.6 554 thirty 28.3 1085 CIF CD69 0 11.6 204.5 thirty 10.2 464.5 % CD25 to CD8+ 0 0.52% 25.95% thirty 0.29% 39.60% % CD69 to CD8+ 0 0.24% 36.40% thirty 0.17% 61.65%

In Tables 5-E, 5-F, FG, and 5-H : Cytokine data from T cell activation and function assays.

Table 5-E Compound 113 (µM) without TKR stimulation Mouse anti-CD3/anti-CD28 T-cell activator Dynabeads
(1:5 granules:cells) IFNγ (ng/ml) 0 1.2 70 thirty 1.2 356 TNFɑ (ng/ml) 0 1.2 92 thirty 1.5 208 Table 5-F Compound 124 (µM) without TKR stimulation Mouse anti-CD3/anti-CD28 T-cell activator Dynabeads
(1:5 granules:cells) IFNγ (ng/ml) 0 1.2 118 thirty 1.2 435 TNFɑ (ng/ml) 0 1.4 101 thirty 1.4 195 Table 5-G Compound 182 (µM) without TKR stimulation Mouse anti-CD3/anti-CD28 T-cell activator Dynabeads
(1:5 granules:cells) IFNγ (ng/ml) 0 25 thirty 189 TNFɑ (ng/ml) 0 92 thirty 135 Table 5-H Compound 260 (µM) without TKR stimulation Mouse anti-CD3/anti-CD28 T-cell activator Dynabeads
(1:5 granules:cells) IFNγ (ng/ml) 0 3.8 139 thirty 3.8 752 TNFɑ (ng/ml) 0 2.0 113 thirty 2.1 207

Example 227. in vivo efficacy of PTPN2 inhibitors in the MC38 tumor model and effects on pharmacodynamic markers

Mice.

All experiments were performed in accordance with the AbbVie Institutional Animal Care and Use Guidelines and the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals in a facility accredited by the Association for the Evaluation and Accreditation of the Care of Laboratory Animals. 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 . The animals were acclimatized in the housing for a period of at least one week prior to the experiments. Animals were examined during the light phase of the regimen 12 hours a day: 12 hours night (light at 0600 hours).

Tumor cell inoculation and processing.

Cells were grown up to 3 passages in vitro. A total of 1×10 ⁵ viable MC-38 cells were inoculated subcutaneously into the right flank of female C57Bl/6 mice (7-12 weeks) 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 reached the required size on day 14, and the mice had an average body weight of ~21 g. The mean tumor volume (VV) at the time of reaching the required size was 116 ± 8 mm ³ . After reaching the required size, processing was started on the same day. Mice were dosed orally twice a day (DS) at 7 am and 5 pm for 21 days. Mice were dosed (300 mg/kg/dose) with one of compounds 124, 182 or vehicle control (n=10-15 mice/group). Compound 124 was formulated in 5% DMSO, 5% Tween 80 (polysorbate 80), 20% PEG-400 and 70% D5W (5% dextrose in water) and dosed at 10 ml/kg. Compound 182 was formulated in 10% ethanol, 30% PEG-400 and 60% Phosal 50 PG and dosed at 10 ml/kg. Tumor volume was calculated three times a week. Tumor length (L) and width (W) measurements were taken with an electronic caliper, and volume was calculated using the following equation: V=L x W ² /2 using Study Director version 3.1.399.22 (Studylog Systems, Inc, CA, USA) . Mice were sacrificed when tumor volume was ≤ 3000 mm ³ or skin ulcerations appeared. Tumor growth inhibition (TGI) was calculated as TGI=1-(mean RO _{time (treatment)} /mean RO _{time (vehicle)} ) for each time when tumor volume was measured. The presented value of RHI _max is the highest value of RTI for any point in time when the volume of tumors in this treatment group was estimated.

Analysis of pSTAT5 by flow cytometry in whole blood of mice.

Whole blood was collected into EDTA powder-coated tubes by heart puncture in mice on day 8 of dosing with the indicated PTPN2/1B inhibitor (2 hours after day 16). doses). 100 µl whole blood was stimulated with 100 ng/ml mouse IL-2 (R&D Systems, Minneapolis, MN, cat# 402-ML) for 20 minutes at 37°C, 5% CO₂. After stimulation, 1.8 ml of pre-warmed BD Phosflow lysis/fixation buffer (BD Biosciences, San Jose, CA) was added for 20 minutes at 37°C. Cells were washed twice with FACS buffer (Dulbecco's PBS with 0.2% BSA) and incubated for 30 minutes 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 hours at room temperature with gentle shaking. The antibodies added were a combination of the following antibodies: 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 sampled on a BD LSRFortessa™ X20 flow cytometer (BD Biosciences, San Jose, CA) analyzed using FLowJo V10 software (FlowJo, Ashland, OR). The mean fluorescence intensity (MFI) of pSTAT5 as a measure of the amount of STAT5 phosphorylated in the CD3+ T cell population was expressed as the fold change for compound-treated versus vehicle-treated animal groups.

Flow cytometry analysis of CD8 T cell staining with granzyme B in mouse spleens.

Mice were sacrificed on day 8 of dosing with the indicated PTPN2/1B inhibitor (2 hours after the 16th doses) and excised spleens. Spleen dissociation was performed using a gentleMACS dissociator (Miltenyi Biotec, Bergisch Gladbach, Germany), red blood cells were lysed, and single cell suspensions were prepared. Splenocytes were stained with Zombie UV™ Fixable Viability Kit (Biolegend, San Diego, CA) diluted in Dulbecco's PBS for 10 minutes at room temperature to exclude dead cells, followed by staining for surface markers for 45 minutes. on ice using the following flow cytometric 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 Set; eBioscience) and stained intracellularly with PE-labeled anti-granzyme B antibody diluted in permeabilization buffer (FoxP3/Transcription Factor Staining Buffer Set; eBioscience, San Diego, CA) for 1 hour on ice. After staining, cells were washed twice with autoMACS running buffer and sampled on a BD LSRFortessa™ X20 flow cytometer (BD Biosciences, San Jose, CA) analyzed using FLowJo V10 software (FlowJo, Ashland, OR). The fold change in the frequency of granzyme B+ cells in the CD8+ T cell population of the compound-treated group compared to the vehicle-treated control group.

Measurement of cytokines in mouse plasma.

Whole blood was collected in sodium heparin by cardiac puncture from mice on day 8 of dosing with the indicated PTPN2/1B inhibitor (2 hours after the 16th doses) and prepared plasma for centrifugation. Plasma cytokines were measured using a Th1/Th2 Cytokine & Chemokine 20-Plex Mouse ProcartaPlex™ Panel 1 (Invitrogen, Carlsbad, CA). IP10 levels were expressed as fold change relative to vehicle control-treated group of animals.

results

It has recently been described that the expression in tumor cells of the phosphatase PTPN2 and its highly homologous equivalent PTP1B is a negative regulator of tumor-directed immune responses. The functional activity of PTPN2, which consists in the inhibition of signaling cascades of external factors in tumor cells, in particular the dephosphorylation of STAT molecules after the IFNγ receptor, has been identified as a significant contribution to the ability of tumor cells to evade or suppress antitumor immune responses. To confirm these findings, specific inhibitors of PTPN2/1B were designed and their ability to inhibit tumor growth and induce antitumor inflammation was tested in an in vivo syngeneic mouse tumor model. Mice were inoculated with MC-38 mouse colon adenocarcinoma cells in the posterior flank. After two weeks of cell growth, oral treatment of DS mice for 21 days with either vehicle or formulations of Compound 124 or Compound 182 was initiated. Both Compound 124 and Compound 182 were well tolerated with no apparent health-related adverse events. At the same time, obvious stasis and a decrease in the size of tumors were observed within 7-10 days in animals that were dosed with compound 124 or compound 182. Ultimately, 50% of mice treated with compound 124 or compound 182 achieved complete cure and a total RDI _{of max} 75% and 94%, respectively (Table 6). Following the discovery of significant antitumor efficacy of Compound 124 and Compound 182, further studies were conducted on the binding of the compounds to the target in vivo, as well as their effect on antitumor immune responses.

IL2 signaling in T cells promotes homeostasis and T cell 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 PTPN2/1B inhibitor is expected to increase STAT5 phosphorylation following IL2 stimulation. To demonstrate in vivo target binding, we measured pSTAT5 levels in whole blood T cells from animals dosed with a PTPN2/1B inhibitor following in vitro whole blood IL2 stimulation. In mice treated with compound 124 or compound 182, pSTAT5 in whole blood T cells was increased by 2.3-fold and 2.1-fold, respectively, compared to vehicle control treated mice (Table 6).

One of the desirable effects of immunotherapy is the induction of functional cytotoxic T cells, which may improve antitumor immunity. In mice treated with Compound 124 or Compound 182, the frequency of functional granzyme B (GzB)-producing cells in the population of cytotoxic CD8+ T cells in the spleen was increased 2.9-fold and 1.8-fold, respectively, compared with animals treated with control carrier (Table 6).

Since a PTPN2/1B inhibitor promotes IFNγ signaling by increasing phosphorylation of JAK and STAT signaling molecules, and IP10 is an IFNγ-inducible protein, a PTPN2/1B inhibitor is expected to increase IP10 production. Plasma levels of IP10 in Compound 124 or Compound 182 treated mice were increased 2.5- and 1.5-fold, respectively, compared to vehicle control treated animals (Table 6).

Table 6: Effect of oral DS dosing with these compounds on tumor growth and translocation of PD markers in the syngeneic MC-38 tumor model. IRO_Max determined throughout the study. PD markers were assessed on the 8th day of dosing (2 hours after the 16th doses). Data are presented as fold change for compound-treated animals compared to vehicle-treated controls.

Compound Tumor growth inhibition (max) compared to vehicle [%] % GzB+ cells among spleen CD8+ T cells
[fold change from carrier] pSTAT5 level in CD3+ T cells from IL2-stimulated whole blood [fold change from vehicle] IP10 in plasma [fold change from vehicle] 124 75 2.9 2.3 2.5 182 94 1.8 2.1 1.5

Equivalents and volume

In the text of the claims, singular forms may mean one or more than one, unless otherwise indicated or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are deemed to be satisfied if one, more than one, or all of the members of the group are present, applicable, or related to a particular product or method, unless otherwise stated or otherwise not obvious from the context. The description of the invention includes embodiments of the invention in which exactly one member of the group is present in, applied to, or otherwise related to a given product or method. The description of the invention includes embodiments of the invention in which more than one of the group of members is present in, applied to, or otherwise related to a given product or method.

In addition, the description covers all variations, combinations and permutations in which one or more of the limitations, elements, provisions and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that depends on another claim may be modified to include one or more of the limitations found in any other claim that depends on the same main claim. When elements are presented as lists, such as in the Markush group format, each subgroup of elements is also described, and any element(s) may be removed from the group. It should be understood that, in general, when a description or aspects of the description are referred to as containing specific elements and/or features, some embodiments of the invention or aspects of the description consist or consist essentially of such elements and/or features. For simplicity, these embodiments of the invention have not been specifically set forth in haec verba in this document. It is also noted that the terms "comprising" and "comprising" are intended to be open-ended and to allow the inclusion of additional elements or steps. When ranges are specified, endpoints are included. In addition, unless otherwise indicated or obvious from the context and knowledge of a person skilled in the art, values that are expressed as ranges can take on any particular value or subrange within the specified ranges in different embodiments of the invention, up to a tenth of the unit of the lower limit range, unless the context clearly indicates otherwise.

This application relates to various issued patents, published patent applications, journal articles and other publications, all of which are incorporated here by reference. If there is a conflict between any of the included links and this description, the description shall take precedence. In addition, any particular embodiment of the present invention that is prior art may be expressly excluded from any one or more claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded, even if the exclusion is not explicitly stated here. Any particular embodiment of the invention may be excluded from any claim for any reason, regardless of whether it is due to prior art.

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

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SEQUENCE LIST

<110> Calico and AbbVie

<120> PROTEIN TYROSINPHOSPHATASE INHIBITORS AND METHODS

THEIR APPLICATIONS

<130>CLS-014WO

<150> US62/688226

<151> 06/21/2018

<160> 3

<170> PatentIn version 3.5

<210> 1

<211> 404

<212> Protein

<213> Artificial

<220>

<223> synthetic peptide

<400> 1

Met Ala Met Pro Thr Thr Ile Glu Arg Glu Phe Glu Glu Leu Asp Thr

1 5 10 15

Gln Arg Arg Trp Gln Pro Leu Tyr Leu Glu Ile Arg Asn Glu Ser His

20 25 30

Asp Tyr Pro His Arg Val Ala Lys Phe Pro Glu Asn Arg Asn Arg Asn

35 40 45

Arg Tyr Arg Asp Val Ser Pro Tyr Asp His Ser Arg Val Lys Leu Gln

50 55 60

Asn Ala Glu Asn Asp Tyr Ile Asn Ala Ser Leu Val Asp Ile Glu Glu

65 70 75 80

Ala Gln Arg Ser Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys

85 90 95

Cys His Phe Trp Leu Met Val Trp Gln Gln Lys Thr Lys Ala Val Val

100 105 110

Met Leu Asn Arg Ile Val Glu Lys Glu Ser Val Lys Cys Ala Gln Tyr

115 120 125

Trp Pro Thr Asp Asp Gln Glu Met Leu Phe Lys Glu Thr Gly Phe Ser

130 135 140

Val Lys Leu Leu Ser Glu Asp Val Lys Ser Tyr Tyr Thr Val His Leu

145 150 155 160

Leu Gln Leu Glu Asn Ile Asn Ser Gly Glu Thr Arg Thr Ile Ser His

165 170 175

Phe His Tyr Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala

180 185 190

Ser Phe Leu Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Asn

195 200 205

Pro Asp His Gly Pro Ala Val Ile His Cys Ser Ala Gly Ile Gly Arg

210 215 220

Ser Gly Thr Phe Ser Leu Val Asp Thr Cys Leu Val Leu Met Glu Lys

225 230 235 240

Gly Asp Asp Ile Asn Ile Lys Gln Val Leu Leu Asn Met Arg Lys Tyr

245 250 255

Arg Met Gly Leu Ile Gln Thr Pro Asp Gln Leu Arg Phe Ser Tyr Met

260 265 270

Ala Ile Ile Glu Gly Ala Lys Cys Ile Lys Gly Asp Ser Ser Ile Gln

275 280 285

Lys Arg Trp Lys Glu Leu Ser Lys Glu Asp Leu Ser Pro Ala Phe Asp

290 295 300

His Ser Pro Asn Lys Ile Met Thr Glu Lys Tyr Asn Gly Asn Arg Ile

305 310 315 320

Gly Leu Glu Glu Glu Glu Lys Leu Thr Gly Asp Arg Cys Thr Gly Leu Ser

325 330 335

Ser Lys Met Gln Asp Thr Met Glu Glu Asn Ser Glu Ser Ala Leu Arg

340 345 350

Lys Arg Ile Arg Glu Asp Arg Lys Ala Thr Thr Ala Gln Lys Val Gln

355 360 365

Gln Met Lys Gln Arg Leu Asn Glu Asn Glu Arg Lys Arg Lys Arg Pro

370 375 380

Arg Leu Thr Asp Thr Glu Asn Leu Tyr Phe Gln Ser His His His His

385 390 395 400

His His His His

<210> 2

<211> 13

<212> Protein

<213> Artificial

<220>

<223> synthetic peptide

<220>

<221> X

<222> (1)..(1)

<223> (Oregon Green)-(NH-CH2-CH2-O-CH2-CH2-O-CH2-CO)-L-threonine

<220>

<221> X

<222> (5)..(5)

<223> O-phospho-L-tyrosine

<220>

<221> X

<222> (13)..(13)

<223> L-lysine-NH2

<400> 2

Xaa Arg Asp Ile Xaa Glu Thr Asp Tyr Tyr Arg Lys Xaa

1 5 10

<210> 3

<211> 339

<212> Protein

<213> Artificial

<220>

<223> synthetic peptide

<400> 3

Met Ala His His His His His His Ser Ser Gly Leu Val Pro Arg Gly

1 5 10 15

Ser His Met Glu Met Glu Lys Glu Phe Glu Gln Ile Asp Lys Ser Gly

20 25 30

Ser Trp Ala Ala Ile Tyr Gln Asp Ile Arg His Glu Ala Ser Asp Phe

35 40 45

Pro Cys Arg Val Ala Lys Leu Pro Lys Asn Lys Asn Arg Asn Arg Tyr

50 55 60

Arg Asp Val Ser Pro Phe Asp His Ser Arg Ile Lys Leu His Gln Glu

65 70 75 80

Asp Asn Asp Tyr Ile Asn Ala Ser Leu Ile Lys Met Glu Glu Ala Gln

85 90 95

Arg Ser Tyr Ile Leu Thr Gln Gly Pro Leu Pro Asn Thr Cys Gly His

100 105 110

Phe Trp Glu Met Val Trp Glu Gln Lys Ser Arg Gly Val Val Met Leu

115 120 125

Asn Arg Val Met Glu Lys Gly Ser Leu Lys Cys Ala Gln Tyr Trp Pro

130 135 140

Gln Lys Glu Glu Lys Glu Met Ile Phe Glu Asp Thr Asn Leu Lys Leu

145 150 155 160

Thr Leu Ile Ser Glu Asp Ile Lys Ser Tyr Tyr Thr Val Arg Gln Leu

165 170 175

Glu Leu Glu Asn Leu Thr Gln Glu Thr Arg Glu Ile Leu His Phe

180 185 190

His Tyr Thr Thr Trp Pro Asp Phe Gly Val Pro Glu Ser Pro Ala Ser

195 200 205

Phe Leu Asn Phe Leu Phe Lys Val Arg Glu Ser Gly Ser Leu Ser Pro

210 215 220

Glu His Gly Pro Val Val Val His Cys Ser Ala Gly Ile Gly Arg Ser

225 230 235 240

Gly Thr Phe Cys Leu Ala Asp Thr Cys Leu Leu Leu Met Asp Lys Arg

245 250 255

Lys Asp Pro Ser Ser Val Asp Ile Lys Lys Val Leu Leu Glu Met Arg

260 265 270

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

<---

Claims (9)

1. Connection, where the connection is

. 2. Connection, where the connection is

, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2, wherein the compound is a pharmaceutically acceptable salt

. 4. The compound according to claim 2, where the compound is a sodium salt

.