Development of molecular imaging probes for carbonic anhydrase-IX using click chemistry

• US 7,829,063 B2
• Filed: 04/07/2008
• Issued: 11/09/2010
• Est. Priority Date: 04/05/2007
• Status: Active Grant

• Current Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Original Assignee: Siemens Medical Solutions USA Incorporated (Siemens AG)
• Inventors: Scott, Peter J. H., Kolb, Hartmuth C., Wang, Bing, Chen, Gang, Zhang, Wei, Mocharla, Vani P., Gangadharmath, Umesh B., Liang, Qianwa, Xia, Chunfang, Chen, Kai, Collier, Thomas Lee, Gao, Zhiyong, Duclos, Brian A., Padgett, Henry Clifton, Zhao, Tieming, Walsh, Joseph C., Karimi, Farhad, Kasi, Dhanalakshmi
• Primary Examiner(s): CHUNG, SUSANNAH LEE
• Application Number:
  US12/099,135
• Publication Number:
  US 20090123372A1
• Time in Patent Office: 946 Days
• Field of Search: 424/1.11, 549/32
• US Class Current: 424/1.11
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 249/06 with aryl radicals directly attached to ring atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C12Q 1/485 involving kinase
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2500/10 involving cells

Abstract

The present application discloses methods for identifying inhibitors with high binding-affinity for the carbonic anhydrase-IX (CA-IX) enzyme using click chemistry and uses the candidates thereof as positron emission tomography (PET) imaging agents.

Claims

1. A compound consisting of the Formula Ia or Ib:

2. The compound of claim 1, wherein the compound is of the Formula Ia, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixtures of stereoisomers thereof.

3. The compound of claim 1, wherein the compound is of the Formula Ib, or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixtures of stereoisomers thereof.

4. The compound of claim 1, wherein the radionuclide is selected from the group consisting of ¹¹C, ¹⁸F, ¹³N and ¹⁵O.

5. The compound of claim 1, wherein X′

is selected from the group consisting of carboxylic acids, sulfonic acids, phosphonic acid and ammonium ion and their respective salts.

6. The compound of claim 1, wherein the X′

comprises a group selected from —

COOH, —

SO₃H, —

PO₃H, —

N(C_1-6alkyl)₃⁺X⁻

wherein X⁻

is a counter anion.

7. The compound of claim 1, wherein:

X is a bond, or is selected from the group consisting of heterocyclyl, aryl, heteroaryl, C_1-6alkyl, C_1-6alkyl wherein 1 or 2 carbon atoms of the C_1-6alkyl is replaced by a —

O—

, —

C(O)—

, —

S—

, —

S(O)—

, —

S(O)₂—

or —

NR′

″

—

where R′

″

is H or C_1-5alkyl, —

NR^o—

C(O)—

CH(R)—

where R^o is H or C_1-5alkyl, and where the C_1-6alkyl is optionally substituted with 1 or 2 substituents selected from the group consisting of —

OH, —

SH, NH₂, heterocyclyl, aryl and heteroaryl.

8. The compound of claim 1, wherein:

each G is independently a bond or is independently selected from the group consisting of substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

9. The compound of claim 1, wherein:

each G is independently a bond or is independently selected from the group consisting of substituted or unsubstituted heterocyclyl, aryl and heteroaryl; and

X′

is selected from the group consisting of a quaternary ammonium salt, imidate salt, thiolate salt, oxonium cation, boron-amine salt, pyridinium salt, —

SO₂H, —

SO₃H, —

PO₃H, —

OPO₃H, N-oxides, —

B(OH)₂, halo, —

CF₃, —

CH₂F, —

CHF₂, —

COOH, halo-C_1-5alkyl, halo-C_1-5alkoxy-;

Z′

—

C_2-6alkyl, Z′

—

C_2-6alkyl-O—

, Z′

—

C_2-6alkyl-S—

, Z′

—

C_2-6alkyl-NH—

, Z′

—

C_2-6alkyl-NH—

C_1-3alkyl-, Z′

—

(CH_2-6alkyl-N(C_1-3alkyl)-C_1-3alkyl-, Z′

(CH₂CH₂—

O)_1-5—

, wherein Z′

is selected from the group consisting of halo, —

CF₃, —

CH₂F, —

CHF₂, aryl and heteroaryl.

10. The compound of claim 1, wherein:

Y is H or is selected from the group consisting of a quaternary ammonium salt, imidate salt, thiolate salt, oxonium cation, boron-amine salt, pyridinium salt, —

SO₂H, N-oxide, —

B(OH)₂, —

COOR″

, —

SO₃R″

, —

P(O)₂OR″ and

—

OP(O)₂OR″

wherein R″

is H or C_1-3alkyl; and

R is H or a side chain of an encoded amino acid, —

C_1-5alkyl-o, m, or p-aryl-(O—

CH₂CH₂)_1-5-halo or —

C_1-5alkyl-o, m, or p-aryl-(CH₂CH₂)_1-5-halo.

11. The compound of claim 1, wherein:

X′

is selected from the group consisting of a quaternary ammonium salt, imidate salt, thiolate salt, oxonium cation, boron-amine salt, pyridinium salt, —

SO₂H, N-oxide, —

B(OH)₂, halo, —

CF₃, —

CH₂F, —

CHF₂, halo-C_1-5alkyl, halo-C_1-5alkoxy-;

Z′

—

C_2-6alkyl, Z′

—

C_2-6alkyl-O—

, Z′

—

C_2-6alkyl-S—

, Z′

—

C_2-6alkyl-NH—

, Z′

—

C_2-6alkyl-N(C_1-3alkyl)-C_1-3alkyl-, Z′

—

(CH₂CH₂—

O)_1-5—

, wherein Z′

is selected from the group consisting of halo, —

CF₃, —

CH₂F, —

CHF₂, aryl and heteroaryl.

12. The compound of claim 1 of the Formula Ia:

13. The compound of claim 1 of the Formula Ia:

14. The compound of claim 13, wherein:

G is selected from the group consisting of a heterocyclyl, aryl and heteroaryl;

n is 1 or 2;

X′

is selected from the group consisting of a quaternary ammonium salt, imidate salt thiolate salt oxonium cation boron-amine salt, pyridinium salt, —

SO₂H, N-oxide, —

B(OH)₂, —

OH, amino, halo, —

COOH, amino-C_1-5alkyl-, halo-C_1-5alkyl, halo-C_1-5alkoxy-;

Z′

—

C_1-6alkyl, Z′

—

C_2-6alkyl-O—

, Z′

—

C_2-6alkyl-NH—

, Z′

—

C_2-6alkyl-NH—

C_1-3alkyl-, Z′

—

C_2-6alkyl-N(C_1-3alkyl)-C_1-3alkyl-, Z′

—

(CH₂CH₂—

O)_1-5—

, wherein Z′

is selected from the group consisting of halo, —

CF₃, —

CH₂F, —

CHF₂;

Y is selected from the group consisting of a quaternary ammonium salt, imidate salt, thiolate salt, oxonium cation, boron-amine salt, pyridinium salt, —

SO₂H, N-oxide, —

B(OH)₂, —

COOR″

, —

SO₃R″

, —

P(O)₂OR″ and

—

OP(O)₂OR″

wherein R″

is H or C_1-3alkyl; and

R is H or a side chain of an encoded amino acid.

15. The compound of claim 1, wherein the compound is:

(R)-2-((S)-3-(4-(2-fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid;

(2S)-2-((2S)-3-(4-(3-fluoro-2-hydroxypropoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid;

(S)-3-(4-(2-fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-(trifluoromethoxy)benzyl)propanamide;

(S)-2-(S)-3-(4-(2-fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(1H-indol-3-yl)propanoic acid;

(S)-2-(S)-3-(4-(2-fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid;

(S)-3-(4-cyanophenyl)-2-(S)-3-(4-(2-fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)propanoic acid;

(S)-methyl 3-(3-(2-fluoroethoxy)benzylthio)-2-(S)-4-hydroxy-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoate;

(R)-3-(3-(2-fluoroethoxy)benzylthio)-2-(R)-4-hydroxy-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid;

(R)-3-(3-(2-fluoroethoxy)benzylthio)-2-(S)-4-hydroxy-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid;

(S)-2-(S)-3-(4-(((4S,5R)-5-(fluoromethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid;

(S)-2-((R)-3-(4-(((4S,5R)-5-(fluoromethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid;

3-(3-(2-fluoroethoxy)benzylthio)-2-(4-hydroxy-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid;

(S)-2-(S)-3-(4-((2S,3R)-4-fluoro-2,3-dihydroxybutoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid;

(S)-2-((R)-3-(4-((2S,3R)-4-fluoro-2,3-dihydroxybutoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid;

(2R)-3-(3-((1-(1-fluoro-3-hydroxypropan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzylthio)-2-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)acetamido)propanoic acid;

(2R)-3-(3-(2-fluoroethoxy)benzylsulfinyl)-2-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)acetamido)propanoic acid;

(S)-3-(3-(2-fluoroethoxy)benzyloxy)-2-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)meth 1-1H-1,2,3-triazol-1-yl)acetamido)propanoic acid;

(2S)-3-(3-(3-fluoro-2-hydroxypropoxy)benzyloxy)-2-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)acetamido)propanoic acid;

(2S)-3-(4-(3-fluoro-2-hydroxypropoxy)phenyl)-2-(R)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid;

(2S)-3-(4-(3-fluoro-2-hydroxypropoxy)phenyl)-2-(R)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid;

(S)-3-(4-(2-fluoroethoxy)phenyl)-2-(R)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid;

(S)-3-(4-(2-fluoroethoxy)phenyl)-2-(R)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid;

(S)-3-(4-(2-fluoroethoxy)phenyl)-2-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)acetamido)propanoic acid;

(2S)-3-(4-(3-fluoro-2-hydroxypropoxy)phenyl)-2-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)acetamido)propanoic acid;

(2S)-3-(4-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)-2-(S)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid; and

(2S)-3-(4-(1-fluoro-3-hydroxypropan-2-yloxy)phenyl)-2-(R)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoic acid.

16. The compound of claim 1, wherein the compound is:

(R)-Methyl 3-(benzylthio)-2-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)acetamido)propanoate;

(R)-3-(3-(2-Fluoroethoxy)benzylthio)-2-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)acetamido)propanoic

(2S)—

N-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)-Methyl 2-((S)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)-3-(4-(trifluoromethyl)phenyl)propanoate;

(S)-Methyl 3-((S)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)-3-(4-(trifluoromethyl)phenyl)propanoate;

(S)-3-(S)-3-Methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid;

(S)-3-Phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-(trifluoromethyl)benzyl)propanamide;

(S)—

N-((5-Methyl-3-phenylisoxazol-4-yl)methyl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)-Ethyl 1-(3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanoyl)piperidine-4-carboxylate;

(2S)—

N((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)-Ethyl 1-(3-(4-(2-Fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanoyl)piperidine-4-carboxylate;

(S)-3-(4-(2-Fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-(trifluoromethyl)benzyl)propanamide;

(S)-1-(3-(4-(2-Fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanoyl)piperidine-4-carboxylic acid;

(S)-Methyl 2-((S)-3-(4-(2-fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(4-(trifluoromethyl)phenyl)propanoate;

(S)-2-(S)-3-Methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid; and

(S)-2-(S)-3-(4-(2-Fluoroethoxy)phenyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid.

17. A compound that is:

6-((1-(2-Morpholinoethyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)—

N-(4-Methylpridin-2-yl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

N-Morpholino-3-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)benzamide;

(S)—

N-Benzyl-4-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)pentanamide;

6-((1-((2R)-3-Methyl-1-(3-methylpiperidin-1-yl)-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)—

N-(2,5-Dimethylbenzyl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)—

N-Cyclohexyl-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)—

N-Benzyl-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-11′

-1,2,3-triazol-1-yl)butanamide;

4-(3-Methoxy-3-oxo-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)benzoic acid;

Propyl 4-(2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)acetamido)benzoate;

6-((1-(2-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(R)—

N-(Biphenyl-4-yl)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

6-((1-(4-((1S,2R)-1,2-Dihydroxyoctyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

6-((1-(7-Chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

6-((1-(6-Hydroxyhexyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

6-((1-((1S,2S)-2-(Cinnamyloxy)-1,2-diphenylethyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)-3-Methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-(thiophen-3-yl)ethyl)butanamide;

6-((1-(2-(2,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

6-((1-(2-(4-(3,5-Dichlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(E)-6-((1-(1-(Styrylsulfonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(E)-6-(1-(1-Cinnamoylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)—

N-(4-Fluorobenzyl)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)—

N-Benzyl-N,3-dimethyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)—

N-(2-((5-((Dimethylamino)methyl)furan-2-yl)methylthio)ethyl)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)-6-((1-(3-Methyl-1-oxo-1-(4-(pyrimidin-2-yl)piperazin-1-yl)butan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)-3-Methyl-N-((5-(pyridin-2-yl)thiophen-2-yl)methyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

6-((1-((S)-1-((R)-2-(Hydroxymethyl)pyrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)-6-((1-(3-Methyl-1-oxo-1-(4-(pyridin-2-yl)piperazin-1-yl)butan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)-Ethyl 2-((S)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)-3-phenylpropanoate;

(S)-Ethyl 3-methyl-2-((S)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)butanoate;

(S)-Methyl 2-((S)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoate;

(S)-3-Methyl-N-(pyridin-2-ylmethyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)—

N-Cyclohexyl-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)—

N-(Cyclopropylmethyl)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)—

N-(3-Hydroxypropyl)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)-3-Methyl-N-((5-methyl-3-phenylisoxazol-4-yl)methyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)-6-((1 (1-(4-(2-Hydroxyethyl)piperazin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)—

N-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)-6-((1-(3-Methyl-1-oxo-1-(4-(pyrrolidin-1-yl)piperidin-1-yl)butan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)—

N-(2-(4-Benzylpiperazin-1-yl)ethyl)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamide;

(S)-Ethyl 3-(1H-indol-3-yl)-2-((S)-3-methyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)butanamido)propanoate;

(S)—

N-(4-Fluorobenzyl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)—

N-Benzyl-N-methyl-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)—

N-(245-((Dimethylamino)methyl)furan-2-yl)methylthio)ethyl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)-6-((1-(1-Oxo-3-phenyl-1-(4-(pyrimidin-2-yl)piperazin-1-yl)propan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)-3-Phenyl-N-((5-(pyridin-2-yl)thiophen-2-yl)methyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

6-((1-((S)-1-(R)-2-(Hydroxymethyl)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)-6-((1-(1-Oxo-3-phenyl-1-(4-(pyridin-2-yl)piperazin-1-yl)propan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(R)-ethyl 3-Phenyl-2-((S)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)propanoate;

(S)-Ethyl 3-methyl-2-((S)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamido)butanoate;

(S)-3-Phenyl-N-(pyridin-2-ylmethyl)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)1H-1,2,3-triazol-1-yl)propanamide;

(S)—

N-Cyclohexyl-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)—

N-(Cyclopropylmethyl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)—

N-(3-Hydroxyprop yl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)-6-((1-(1-(4-(2-Hydroxyethyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)—

N-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(2S)—

N((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)-6-((1-(1-(4-(2-Hydroxyethyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)—

N-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)-6-((1-(1-(4-(2-Hydroxyethyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)benzo[d]thiazole-2-sulfonamide;

(S)—

N-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-3-phenyl-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide;

(S)—

N,N,N-Trimethyl-2-oxo-2-(6-oxo-5-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-6-(4-(trifluoromethyl)benzylamino)hexylamino)ethanaminium;

(S)-3,10-Dioxo-4-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-1-(4-(trifluoromethyl)phenyl)-13,16,19,22,25-pentaoxa-2,9-diazaoctacosan-28-oic acid;

(S)-4-Oxo-4-(6-oxo-5-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-6-(4-(trifluoromethyl)benzylamino)hexylamino)butanoic acid;

(S)-4-(6-(4-(Ethoxycarbonyl)cyclohexyl)-6-oxo-5-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)hexylamino)-4-oxobutanoic acid; and

(S)-6-(S)-2-Amino-3-hydroxypropanamido)-2-(4-((2-sulfamoylbenzo[d]thiazol-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-(trifluoromethyl)benzyl)hexanamide hydrochloride.

18. A compound of Formula:

19. A compound of claim 18, wherein:

wherein G is phenyl;

n is 1;

X′

is FCH₂CH₂O—

or ¹⁸FCH₂CH₂O—

;

Y is —

COOH;

R is isopropyl; and

Z is —

CH₂O—

;

or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixtures of stereoisomers thereof.