Long-residence ca9 ligands and radioisotope carriers for inhibition, visualization and irradiation of ca9-expressing tumors

Abstract

Described herein are heteroaryl compounds including aryl sulfonamide compounds that bind carbonic anhydrase 9 (CA9); derivatives of such heteroaryl compounds that can bind metal radioisotopes; pharmaceutical compositions containing them; methods of making them; and their use in treating certain diseases or imaging a subject suffering from such diseases.

Description

WSGR Docket No. 20012-705.601LONG-RESIDENCE CA9 LIGANDS AND RADIOISOTOPE CARRIERS FOR INHIBITION, VISUALIZATION AND IRRADIATION OF CA9-EXPRESSING TUMORSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 695,077, filed September 16, 2024, which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates to certain aryl sulfonamide compounds that bind carbonic anhydrase 9 (CA9); derivatives of such compounds that can bind metal radioisotopes; pharmaceutical compositions containing them; methods of making them; and their use in various methods, including the visualization and irradiation of CA9-expressing tumors, and the treatment of one or more disorders, including cancers, inflammatory and other conditions and diseases involving CA9.BACKGROUND

[0003] Carbonic anhydrase isoenzyme IX (CAIX) belongs to the carbonic anhydrase (CA) family of fifteen zinc metalloenzyme isoforms in humans. Among the 12 catalytically active isoforms, four of them (CAIV, CAIX, CAXII and CAXIV) are localized to the plasma membrane and five (CAI, CAII, CAIII, CAVII and CAXIII) are expressed in the cytosol. CAVI is secreted by the salivary and mammary glands, while CAVA and CAVB are restricted to the mitochondria. The rest three cytosol CAs (CAVIII, CAX, CAXI) are catalytically inactive.1These human CAs also differ by enzymatic kinetic properties and distributions in the organs and tissues. CAIX expression is restricted to the epithelial cells of the stomach and gallbladder in healthy tissues,2,3but ectopically induced in various human tumors including lung,4pancreatic,5breast,6cervix,7bladder,8ovarian,9, had and neck,10colorectal,11and esophageal squamous cell carcinoma12in response to hypoxia and acidosis of the tumor microenvironment (TME). CAIX expression is regulated by hypoxia-inducible factor 1 alpha (HIFl-a).13Under physiological normoxic condition, HIFl-a is prolyl hydroxylated by Egl nine homologs (EGLNs) prolyl hydroxylases (PHDs) to promote interaction with von Hippel-Lindau tumor-suppressor gene protein pVHL, leading to rapid ubiquitination and proteasome degradation.14,15However, PHD activities are strictly oxygen dependent. Under oxygen stress in TME, HIF-la is released from VHL and its accumulation leads to activation of cellular responses to hypoxia, including overexpression of CA9.16In the majority cases of clear cell renal cell carcinoma (ccRCC), CAIX is constitutively upregulated on the tumor cell surface even under normoxic condition, driven by the accumulation of HIF-la due to mutations that inactivate p VHL.17WSGR Docket No. 20012-705.601

[0004] Tumor cells in the hypoxic region increase consumption of glucose through glycolytic pathway to convert into lactic acid and produce ATP as the energy source. Even in the regions where sufficient oxygen is available, cancer cells can metabolize significantly more glucose into lactic acid through aerobic glycolysis (Warburg Effect) in addition to mitochondrial respiration, resulting in tumor acidosis from constant and excessive production of metabolic acids.18Increased concentration of protons generated inside the tumor cells needs to be promptly removed for cells to survive at pH 7.2-7.4 intracellularly. CAIX, coordinating with acid / base transporters, plays a critical role in regulating both intracellular and extracellular pH by catalyzing reversible hydration of CO2 to HCO3 and H+.19The extracellular portion of CAIX comprises a catalytic domain and a unique N-terminal proteoglycan-like domain (PG domain), which functions as a proton buffer. CAIX is therefore most active around pH 6.8, close to tumor microenvironment.20’21Hydration reaction is favored when pH is above 6.8 to produce more proton and dehydration proceeds when pH is reduced to less than 6.8 to protect tumor cells from over acidification while creating an environment more detrimental to normal cells, including immune cells with controlled extracellular acidosis.21CAIX has been reported to interact with Na+ / HCO3- transporters to import HCO3- and neutralize intracellular H+.22CAIX also forms transport metabolon with MCTs to facilitate removal of Lactate / proton, protecting tumor cells from intracellular acidosis.23The regulation of both intracellular and extracellular pH by CAIX creates a tumor microenvironment that promotes tumor survival and progression. High expression of CAIX in various tumors correlates to poor survival, higher risk of metastasis and resistance to various therapies including chemo, radiation therapy, and immunotherapy.24'26

[0005] CAIX has been an attractive anti-cancer target and different modalities targeting CAIX have been explored over the past decades. Small molecule inhibitors with various mechanisms of action targeting enzymatic activity were developed.27However, selectivity toward CAIX was difficult to achieve due to structural homology of the catalytic domain between CAIX and other CA isoforms that are expressed on various normal tissues. CAIX specific monoclonal antibody (mAbs) has advanced into clinics as an imaging agent and / or therapeutics. The chimeric IgGl mAb Girentuximab (cG250) that targets PG region in the ectodomain (ECD) of CAIX demonstrated clinical efficacy toward ccRCC patients, functioning through antibody-dependent cell-cytotoxicity (ADCC).28-30The antibody has been linked to various radiotracers such as124I,i nIn or89Zr to develop imaging agents, with high PPV in detecting both primary and metastatic ccRCC in clinical trials.31-33The radionucleotide177Lu conjugated cG250 also showed clinical benefits in treating metastatic ccRCC patients.34However, given the size of the antibody that causes slow penetration into the tumor and a slow clearance, patients are burdened with waiting for 3-7 days to achieve optimal imaging contrast, and the therapeutic potential of177LuWSGR Docket No. 20012-705.601 conjugated cG250 is limited by the myelotoxicity observed in most patients due to systemic accumulation,34restricting further development of full antibody-based theranostic agents. Additionally, existing CA-targeting therapeutic agents are plagued by their short residence time in the target cell / tissue, thereby limiting the radio-dose that can be delivered by these agents and their abilities to effectively treating malignant cells / tissues. Given the poor selectivity and the short residence nature of existing CA-targeting diagnostic and / or therapeutic agents, there remains a need for selective and long-residence CA-targeting diagnostic and / or therapeutic agents.SUMMARY

[0006] Without wishing to be bound by any particular theory, the present disclosure recognizes that compounds and compositions provided herein demonstrate high specificity of CA9 over other members of the CA family and / or long-residence time in malignant cells / tissues. Among other things, the present disclosure provides various compounds and compositions that are suitable for radiolabeling. In some embodiments, a compound or composition provided herein is used for radio-imaging (e.g., a radiotracer). In some embodiments, a compound or composition provided herein is used for diagnosis. In some embodiments, a compound or composition provided herein is used for therapy. The first aspect of the present disclosure is a compound of Formula I:Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:G is N or CR10; each R1is independently H, halogen, -CF3, -CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -NR2R3, -C(O)NR2R3, -NR2C(NH)NR2R3, -S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O- Ci-C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein said Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10- membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;WSGR Docket No. 20012-705.601 each R2is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, -(Ci-Ce alkyl)-(Ce-Cio aryl), -(Ci-Cs heteroalkyl)-(Ce- C10 aryl), -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl), -(Ci-Cs heteroalkyl)-(5- to 10- membered heteroaryl), -(Ci-Ce alkyl)-(3- to 10-membered heterocycloalkyl), -(Ci-Cs heteroalkyl)-(3- to 10-membered heterocycloalkyl), or 3- to 10-membered heterocycloalkyl, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R3is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), or -C(0)0-(C6-Cio aryl), wherein said Ci-C6alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; orR2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl, wherein said 4- to 8-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Rlb; each R4is independently H, deuterium, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each Q is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -S-, -S(O)-, -S(O)2- -C(R5)=C(R5)-, — C=C— , an amino acid or a derivative thereof, Ce-Cio arylene, 5- to 10- membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R5is independently H, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or an albumin-binding moiety, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-memberedWSGR Docket No. 20012-705.601 heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, wherein each said albuminbinding moiety is independently selected from the group consisting of:wherein * indicates a point of attachment; each R6is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), -C(0)0-(C6-Cio aryl), or said albuminbinding moiety described above, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;R10is independently H, D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ci-Ce heteroalkyl, -NR2R3, CN or NCh, wherein each C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4 alkyl)2 or CN, or R10is R1; each Rlais independently deuterium, halogen, -CN, -OH, -OCH3, C1-C4 haloalkyl, - OS(O)(Ci-C4alkyl), -OS(0)(C6-Cio aryl),-(CH2)kC(O)OH, -(CH2)kC(O)O(Ci-C4alkyl), - (CH2)kC(O)(Ci-C4 alkyl), or -NR2R3, or two Rla, together with the atoms to which they are attached, form a 4- to 6-membered heterocylyl, wherein each C1-C4 alkyl, Ce-Cio aryl, or 4- to 6- membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4alkyl)2or CN;WSGR Docket No. 20012-705.601 each Rlbis independently deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH, oxo, -C(O)NR2R3, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, or -NR2R3, where each said C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy is optionally substituted by 1 or 2 OH, Ci-C2alkoxy, Ci-C2haloalkoxy, or -NR2R3; each Rlcis independently deuterium, halogen, -CN, -C(O)OH, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) OCi- C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) C1-C4 alkyl, C1-C4 haloalkoxy, -OH, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4 alkyl)kNR2C(NH)NR2R3, or -NR2R3, where each said C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is optionally substituted by 1 or 2 -OH, halogen, Ci-C2alkoxy, Ci-C2haloalkoxy, or -NR2R3; each k is independently 0, 1, 2, or 3; each m is independently an integer from 2 to 25; each n is independently 1, 2, or 3;Y is H, R1, or -LL-Z;LL is a bond or a divalent linker connecting Q and Z; andZ is (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye.

[0007] The second aspect of the present disclosure is a compound of Formula II:Formula II or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:G is N or CR10; each R1is independently H, halogen, -CF3, -CN, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -NR2R3, -C(O)NR2R3, -NR2C( H)NR2R3, -S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O- C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3,WSGR Docket No. 20012-705.601 or -CH(R4)NR2R3, wherein said Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10- membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R2is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, -(Ci-Ce alkyl)-(Ce-Cio aryl), -(Ci-Cs heteroalkyl)-(Ce- C10 aryl), -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl), -(Ci-Cs heteroalkyl)-(5- to 10- membered heteroaryl), -(Ci-Ce alkyl)-(3- to 10-membered heterocycloalkyl), -(Ci-Cs heteroalkyl)-(3- to 10-membered heterocycloalkyl), or 3- to 10-membered heterocycloalkyl, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R3is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), or -C(0)0-(C6-Cio aryl), wherein said Ci-C6alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; orR2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl, wherein said 4- to 8-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Rlb; each R4is independently H, deuterium, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each Q is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -S-, -S(O)-, -S(O)2- -C(R5)=C(R5)-, — C=C— , an amino acid or a derivative thereof, Ce-Cio arylene, 5- to 10- membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;WSGR Docket No. 20012-705.601 each R5is independently H, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or an albumin-binding moiety, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, wherein each said albuminbinding moiety is independently selected from the group consisting of:wherein * indicates a point of attachment; each R6is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), -C(0)0-(C6-Cio aryl), or said albuminbinding moiety described above, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;R10is independently H, D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ci-Ce heteroalkyl, -NR2R3, CN or NCh, wherein each C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4 alkyl)2 or CN, or R10is R1; each Rlais independently deuterium, halogen, -CN, -OH, -OCH3, C1-C4 haloalkyl, - OS(O)(Ci-C4alkyl), -OS(0)(C6-Cio aryl),-(CH2)kC(O)OH, -(CH2)kC(O)O(Ci-C4alkyl), - (CH2)kC(O)(Ci-C4 alkyl), or -NR2R3, or two Rla, together with the atoms to which they are attached, form a 4- to 6-membered heterocylyl, wherein each C1-C4 alkyl, Ce-Cio aryl, or 4- to 6-WSGR Docket No. 20012-705.601 membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(CI-C4 alkyl), N(CI-C4alkyl)2or CN; each Rlbis independently deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH, oxo, -C(O)NR2R3, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, or -NR2R3, where each said C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy is optionally substituted by 1 or 2 OH, Ci-C2alkoxy, Ci-C2haloalkoxy, or -NR2R3; each Rlcis independently deuterium, halogen, -CN, -C(O)OH, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) OCi- C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) C1-C4 alkyl, C1-C4 haloalkoxy, -OH, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4 alkyl)kNR2C(NH)NR2R3, or -NR2R3, where each said C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is optionally substituted by 1 or 2 -OH, halogen, Ci-C2alkoxy, Ci-C2haloalkoxy, or -NR2R3;E is a bond, carbon, nitrogen, or a 3- to 14-membered ring system;J is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -O-CH2-CH2-, -CH2-O- CH2-, -CH2-CH2-O-, -S-, -S(O)-, -S(O)2-, -C(R5)=C(R5)-, -C=C-, an amino acid or derivative thereof, Ce-Cio arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each k is independently 0, 1, or 2; each m is independently an integer from 2 to 25; each n is independently 1, 2, or 3; p is an integer from 2 to 25; q is 2, 3, or 4; andZ is (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye.WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601

[0009] A third aspect of the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] A fourth aspect of the present disclosure provides a method of treating a disease or disorder in a subject, the method comprising: administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0011] A fifth aspect of the present disclosure provides a method of optical imaging or diagnostic imaging of a biological tissue that expresses carbonic anhydrase IX (CA9), the method comprising: (a) contacting the biological tissue of a subject with a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein; and (b) detecting an optical signal indicative of cells that overexpress CA9 in the biological tissue.

[0012] A sixth aspect of the present disclosure provides a method of imaging a tumor tissue that expresses carbonic anhydrase IX (CA9), the method comprising: (a) contacting the tumor tissue of a subject with a compound disclosed here or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein; (b) detecting an optical signal indicative of cells that overexpress CA9 in the tumor tissue.INCORPORATION BY REFERENCE

[0013] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.WSGR Docket No. 20012-705.601BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:

[0015] FIG. 1 shows results after female nude mice bearing SK-RC-52 xenografts were intravenously injected with a compound of the present disclosure.

[0016] FIG. 2 shows tumor volume and survival rate of SK-RC-52 tumor bearing mice after injection of [177Lu]-Example 211.

[0017] FIG. 3 shows tumor volume and survival rate of SK-RC-52 tumor bearing mice after injection of [225 Ac] -Example 211.

[0018] FIG. 4 shows body weight of SK-RC-52 tumor bearing mice after injection of [225 Ac]- Example 211.DETAILED DESCRIPTION

[0019] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0020] Our effort is focused on developing a small molecule based and CAIX selective imaging and therapeutic agent to overcome these limitations. The present disclosure may be understood more readily by reference to the following detailed description of the aspects and embodiments of the invention, as well as the Examples described herein. It is to be understood that the disclosure is not limited to specific synthetic methods of making the compounds described, and that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0021] Each of the embodiments described herein may be combined with any other embodiment s) described herein not inconsistent with the embodiment(s) with which it is combined. Any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds or salts herein. Each of the embodiments described herein envisions within its scopeWSGR Docket No. 20012-705.601 pharmaceutically acceptable salts of the compounds, stereoisomers of the compounds, and pharmaceutically acceptable salts of the stereoisomers described herein.Definitions

[0022] As used herein, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise.

[0023] When a range of values is provided, it is to be understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that stated range is encompassed within the scope of the present disclosure. Where the stated range includes upper or lower limits, ranges excluding either of those included limits are also included in the present disclosure. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0024] As used herein, the term “about” or “nearly” when referring to a number or a numerical range means that the number or numerical range generally referred to is within + / - 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the stated number or numerical range.

[0025] As used herein, the term “Ci-Cs alkyl” generally refers to a straight or branched hydrocarbon chain having from 1 to 8 carbon atoms, and the straight or branched hydrocarbon chain is attached to the rest of the molecule by a single bond. Likewise, an alkyl group comprising up to 3 carbon atoms is a C1-C3 alkyl group, an alkyl group comprising up to 6 carbon atoms is a Ci-Ce alkyl group. Examples of a Ci-Ce alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1 -ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3- methylpentyl, 2-m ethylpentyl, 1 -methylpentyl, 3, 3 -dimethylbutyl, 2,2-dimethylbutyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3 -dimethylbutyl, and 2-ethylbutyl. In some instances, a substituent of an alkyl group is specifically indicated. For example, “cyanoalkyl” refers to an alkyl group substituted with at least one cyano substituent.

[0026] The alkyl group may be optionally substituted with a C1-C3 alkoxy group. Examples include, but are not limited to, methoxyethyl, methoxypropyl, methoxyisopropyl, ethoxyethyl, ethoxypropyl, ethoxyisopropyl, propoxyethyl, propoxypropyl, and propoxyisopropyl.

[0027] The alkyl group may be optionally substituted with a C3-C6 cycloalkyl group. Examples include, but are not limited to, 1 -methylcyclopropyl, 1 -methylcyclobutyl, and 1- methylcyclohexyl.

[0028] The alkyl group may be optionally substituted with 1 to 4 Rlagroup as defined elsewhere in this disclosure.WSGR Docket No. 20012-705.601

[0029] As used herein, the term “Ci-Ce alkoxy” generally refers to a radical of the formula -OR wherein R is a Ci-Ce alkyl group as defined. Likewise, an alkoxy group comprising up to 4 carbon atoms is a C1-C4 alkoxy group. Examples of Ci-Ce alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1 -ethylpropoxy, n-hexyloxy, isohexyloxy, 4- methylpentoxy, 3 -methylpentoxy, 2-methylpentoxy, 1 -methylpentoxy, 3.3 -dimethylbutoxy, 2,2- dimethylbutoxy, 1,1 -dimethylbutoxy, 1,2-dimethylbutoxy, 1.3 -dimethylbutoxy, 2,3- dimethylbutoxy, and 2-ethylbutoxy.

[0030] The C1-C4 alkoxy group and Ci-Ce alkoxy group may be optionally substituted with a Ci- C3 alkoxy group. Examples include, but are not limited to, methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxyisopropoxy, ethoxymethoxy, ethoxy ethoxy, ethoxypropoxy, ethoxyisopropoxy, propoxymethoxy, propoxy ethoxy, propoxypropoxy, and propoxyisopropoxy.

[0031] As used herein, the term “C3-C6 cycloalkyl” generally refers to a monocyclic nonaromatic radical having from 3 to 6 ring atoms, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Likewise, a cycloalkyl group comprising from 3 to 10 carbon atoms in the ring is a C3-C10 cycloalkyl group. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “cycloalkenyl” as used herein generally refers to a group that comprises one or more unsaturated rings in which all ring members are carbon. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted.

[0032] As used herein, the term “alkenyl” generally refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C2-8 alkenyl, C2-6 alkenyl and C2-4 alkenyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively, including, for example, ethenyl, allyl or isopropenyl. The term “alkynyl” as used herein generally refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond.

[0033] As used herein, the term “halogen” or “halide” generally refers to fluorine, chlorine, bromine, and iodine. The term “haloalkyl” as used herein generally refers to an alkyl group that is substituted with one or more independently chosen halogens (e.g., “Ci-Ce haloalkyl” groups have from 1 to 6 carbon atoms and at least one halogen). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fluorom ethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; 2,2,2-trifluoroethyl;WSGR Docket No. 20012-705.6011,2-difluoroethyl; 3-bromo-2-fluoropropyl; 1,2-dibromoethyl; and 1,2,2,2-tetrafluoro-l- trifluoromethyl-ethyl. Similarly, the term “haloalkoxy” as used herein generally refers to an alkoxy group that is substituted with one or more independently chosen halogens (e.g., “Ci- C4 haloalkoxy” group refers to a C1-C4 alkoxy group substituted by at least one halogen).

[0034] As used herein, the term “heteroalkyl” generally refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. In some instances, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, or combinations thereof. In some instances, a carbon atom or heteroatom is optionally oxidized (e.g., - C(O)OCH2-, -CH2OCH2-, -CH2S(O)2NHCH2-, -NHC(O)NHCH2-, -CH2NHC(O)CH2-). Further examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -O(CH2)nCH3, - O(CH2)nO(CH2)mCH3, -O(CH2)nCH2OH, -O(CH2)nO(CH2)mCH2OH, -O(CH2)nCH2OS(O)2Ar, - O(CH2)nO(CH2)mCH2OS(O)2Ar, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3, n is independently an integer of 2 to 6, m is independently an integer of 0 to 5, and Ar is unsubstituted or substituted Ce-Cio aryl. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.

[0035] The terms “heterocyclic” or “heterocycle” or “heterocyclyl” or “cycloheteroalkyl” or “heterocycloalkyl” as used herein generally refer to a ring structure (monocycle or polycycle) containing 3-12 ring atoms (3-12 membered heterocycle), 3-8 ring atoms (3-8 membered heterocycle or 3-8 membered cycloheteroalkyl), 3-6 ring atoms (3-6 membered heterocycle or 3- 6 membered cycloheteroalkyl), or 5-6 ring atoms (5-6 membered heterocycle or 5-6 membered cycloheteroalkyl), in which at least one ring atom is carbon, and at least one ring atom is a heteroatom selected from N, O, and S, or a heteroatom group selected from C(=O), S(=O), and S(=O)2. A heterocyclic group may be aromatic or non-aromatic. Piperidine and oxetane are nonlimiting examples of non-aromatic heterocycles. Thiazole and pyridine are non-limiting examples of aromatic heterocycles. Other examples of heterocycle include: aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam,WSGR Docket No. 20012-705.601 caprolactam, butyrolactone, valerolactone and caprolactone. Similarly, the term “cycloheteroalkenyl” refers to a monocycle or polycycle ring structure comprising carbon atom(s) and heteroatom(s) / heteroatom group(s), wherein the cycloheteroalkenyl comprises at least one C=C double bond, at least one ring atom that is carbon, and at least one ring atom that is a heteroatom selected from N, O, and S or a heteroatom group selected from C(=O), S(=O), and S(=O)2. Unless stated otherwise specifically in the specification, a heterocycle or heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe.

[0036] As used herein, the term “aryl” generally refers to an all-carbon monocyclic or fused- ring polycyclic groups of 6 to 10 (Ce-io aryl) having a completely conjugated pi-electron system. Examples include, but are not limited to, phenyl, naphthalenyl, tetrahydronaphthyl, indanyl, biphenyl, and anthracenyl. The aryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and -NRXRY, wherein Rxand RYare independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-membered heteroalicyclic ring. Illustrative substituted alkyl group include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, aminoethyl, hydoxymethyl, methoxymethyl, 2-fluoroethyl, and 2-methoxyethyl, etc.

[0037] The term “heteroaryl” as used herein generally refers to an aromatic group in which at least one aromatic ring comprises at least one heteroatom selected from N, O and S. Heteroaryls include, for example, 5- to 12-membered heteroaryls, 5- tolO-membered heteroaryls, 5- to 7- membered monocyclic structures or 7- to 12-membered bicyclic structures. The number of heteroatoms in a heteroaryl can be 1, 2, 3, 4, or more. Examples include, but are not limited to, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine-2(lH)-keto, pyridine- 4(lH)-keto, pyrrolyl, pyrazolyl, thiazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, 1,2,5-oxadiazolyl, imidazolyl, furanyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl. The heteroaryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto,WSGR Docket No. 20012-705.601 alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and - NRXRY, with Rxand RYas defined above.

[0038] As used herein, the term “amino” generally refers to primary amino group (-NH2), / — N secondary amino group (-NH-), and tertiary amino group ( \).

[0039] As used herein, the term “alkylamino” generally refers to a secondary or tertiary amine that has the general structure -NH-R1or -N(R1)(R2), respectively, wherein R1and R2are selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Such alkylamino groups include, but are not limited to, mono- and di-(Ci-6 alkyl)amino groups, in which each C1-6 alkyl may be the same or different. In this case, the definition of “alkyl” as used in the term “alkylamino” differs from the definition of “alkyl” used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups.

[0040] The terms “substituent” and “substituted,” as used herein, generally denote that a molecular moiety is covalently bonded to an atom within a molecule of interest. For example, a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents of aromatic groups are generally covalently bonded to a ring carbon atom. A straight chain substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of a straight chain.

[0041] As used herein, the terms “optional” or “optionally” generally refer to that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either alkyl or substituted alkyl as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono- substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, - CF2CH3, -CFHCHF2, etc ).

[0042] As used herein, the terms “optionally substituted” or “substituted” generally refers to that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, oxo, -NH2, -NH(alkyl), -N(alkyl)2, -OH, - CO2H, -CO2alkyl, - C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, - S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide,WSGR Docket No. 20012-705.601 arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are independently selected from D, halogen, -CN, oxo, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, - CO2(Ci-C4alkyl), -C(=O)NH2, -C(=O)NH(CI-C4alkyl), -C(=O)N(CI-C4alkyl)2, -S(=O)2NH2, - S(=O)2NH(CI- C4alkyl), -S(=O)2N(CI-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2CI-C4 alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CHs)2, -NH(cyclopropyl), -CH3, - CH2CH3, -CF3, -OCH3, and -OCF3.

[0043] As used herein, the term “amino acid” generally refers to naturally occurring and nonnatural or unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally encoded amino acids are the 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) and pyrolysine and selenocysteine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, by way of example only, an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and a functional R group. Such analogs may have modified R groups (by way of example, norleucine) or may have modified peptide backbones while still retaining the same basic chemical structure as a naturally occurring amino acid. Non-limiting examples of amino acid analogs include homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Amino acids may be referred to herein by either their name, their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. When an amino acid is used as a component of a linker, the points of attachment may be at the amino group or the carboxylic group, or the side chain. When used as a part of a linker, one or more amino acids may be linked consecutively or used individually. A derivative of an amino acid generally refers to a protective form of an amino acid, such as, for example, an amino-protected, a thiol -protected, a hydroxylprotected, or a carboxylic acid-protected form of an amino acid. Such a derivative of amino acid may comprise one or more protecting groups for the indicated -NH2, -SH, -OH, or CO2H functional group.

[0044] As used herein, the term “leaving group” generally refers to molecular fragment or stable species that can be detached from a molecule in a bond-breaking step. The leaving group, in accordance with the specification, is not particularly limited. The ability of a leaving group to depart is correlated with the pKa of the conjugate acid, with lower pKa being associated with better leaving group ability. Examples of leaving group include, without limitation, halide or aWSGR Docket No. 20012-705.601 sulfonate. Halides is as defined above. Examples of sulfonates can include, without limitation, nonaflate, tritiate, fluorosulfonate, tosylate, mesylate or besylate. In one embodiment, for example and without limitation, the leaving group is chloride, mesylate or tosylate. The functional groups that can be converted into leaving groups, in accordance with the specification, are not particularly limited. In one embodiment, for example the functional group can be a hydroxy group that can be converted into a leaving group as described above.

[0045] As used herein, the terms “linker” or “divalent linker” generally refer to a molecule that joins two other molecules, either covalently, or through ionic, van der Waals or hydrogen bonds. In some cases, the linker uses covalent bonds to join the two other molecules. The term “cleavable linker” as used herein generally refers to a linker that can be degraded or otherwise severed to separate the two components connected by the cleavable linker. Cleavable linkers are generally cleaved by enzymes, typically peptidases, proteases, nucleases, lipases, and the like. Cleavable linkers may also be cleaved by environmental cues, such as, for example, changes in temperature, pH, salt concentration, etc., when there is such a change in environment following transcytosis of the compound disclosed herein across a polarized epithelial membrane.

[0046] The term “pharmaceutically acceptable” as used herein generally refers to a form of the compound that is safe for administration to a subject. For example, a free base, a salt form, a solvate, a hydrate, a prodrug or derivative form of a compound described herein, which has been approved for mammalian use, via oral ingestion or any other route of administration, by a governing authority or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.

[0047] Included in the compounds of Formulas I and II are the pharmaceutically acceptable salt forms of the free-base compounds. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. For example, Berge et al. describes pharmaceutically acceptable salts in detail in Pharmaceutical Sciences (1977) 66: 1- 19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Inorganic acids from which salts can be derived include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Examples of pharmaceutically acceptable, nontoxic acid addition salts areWSGR Docket No. 20012-705.601 salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0048] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and other amine salt. Inorganic bases from which salts can be derived include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, but are not limited to, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, examples include, but are not limited to, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is ammonium, potassium, sodium, calcium, or magnesium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium,WSGR Docket No. 20012-705.601 calcium, and magnesium salts. Bis salts (i.e., two counterions) and higher salts (e.g., three or more counterions) are encompassed within the meaning of pharmaceutically acceptable salts.

[0049] As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate.” Other solvates include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide. Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

[0050] As used herein, and unless otherwise specified, “prodrug” refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. A discussion of prodrugs is provided in Higuchi, T., et al , “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active Formulas I and II in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, can be prepared by modifying functional groups present in the active Formulas I and II in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active Formulas I and II is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.

[0051] The term “isomers” as used herein generally refers to different compounds that have the same molecular formula, including any and all geometric isomers and stereoisomers. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. For example, “isomers” include geometric double bond cis- and trans-isomers, also termed E- and Z- isomers; R- and S-enanti omers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure, unless specified otherwise. As used herein, the term “tautomer” is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogenWSGR Docket No. 20012-705.601 atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).

[0052] As used herein, the term “moiety” generally refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0053] As used here, the term “radiolysis” generally refers to a chemical reaction that is caused by ionizing radiation and that is capable of initiating or accelerating mechanisms of degradation of the radiopharmaceutical. For example, the decay of radionuclides of a radiopharmaceutical drug can be accompanied by emission of energy in the form of alpha, beta and / or gamma radiations. The energy can break chemical bonds of the radiopharmaceutical drug and can generate reactive chemical species from the surrounding solvent molecules, which may further decompose the radiopharmaceutical drug directly and / or indirectly.

[0054] As used herein, the term “medical imaging” refers to the means of acquiring and restoring images of the human or animal body from various physical phenomena such as the absorption or emission of photons (e.g., visible, infrared, X-rays, gamma rays), nuclear magnetic resonance, ultrasound wave reflection or radioactivity. According to one embodiment, the term “medical imaging” refers to X-ray imaging, MRI (Magnetic Resonance Imaging), single photon emission tomography (TEMP or SPECT for “Single Photon Emission Computed Tomography”), positron emission tomography (PET) and luminescence. In some embodiments, the medical imaging method is X-ray imaging. SPECT if the radiopharmaceutical comprises a gamma emitter and PET if the radiopharmaceutical comprises a beta+ emitter or a positron emitter.

[0055] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18P, and36C1, respectively. As is understood by those skilled in the art, a description of e.g., hydrogen in the present disclosure encompasses a description of isotopes of hydrogen, such as2H or3H. For example, when a variable group as described herein comprises hydrogen, the present disclosure encompasses a description that such a variable groupWSGR Docket No. 20012-705.601 comprises deuterium or2H at the corresponding position. For example, when in some embodiments, R1is -N(Ci-Ce alkyl)2, it encompasses a description of R1group wherein the Ci- Ce alkyl moiety is deuterated (e.g., mono-deuterated, double-deuterated, triple-deuterated, etc.). In a further example, a description of -NHCH3 encompasses a description of -NHCD3 and other deuterated variants of such group. Compounds described herein, and the pharmaceutically acceptable salts thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon- 14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements

[0056] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1 %, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein.

[0057] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0058] In some embodiments, the compound(s) of Formulas I and II, is used to treat a subject by administering the compound(s) as a pharmaceutical composition. To this end, the compound(s), in one embodiment, is combined with one or more pharmaceutically acceptable excipients, including carriers, diluents or adjuvants, to form a suitable composition, which is described in more detail herein.

[0059] The term “excipient” as used herein generally refers to any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and / or administration purposes.

[0060] The term “diluent” as used herein generally refers to an agent used as filler in order to achieve the desired composition volume or weight. The diluent may be present in the pharmaceutical composition within granules in the form of a single compound or in the form of a mixture of compounds. Non-limiting examples of diluent include lactose, starch,WSGR Docket No. 20012-705.601 pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, dextrose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose.

[0061] The term “adjuvant,” as used herein generally refers to any substance or mixture of substances that increases the efficacy or potency of a compound disclosed herein on a target where the adjuvant is used together with the compound disclosed herein. However, when the adjuvant is used alone, no pharmacological effect is observed on the same target.

[0062] The phrase “effective amount” as used herein generally refers to quantifying the amount of each agent, which can achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. The effective amount, in one embodiment, is administered in a single dosage form or in multiple dosage forms.

[0063] The terms “treat,” “treating,” “treatment,” and “therapy” as used herein generally refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy. Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals. Treatment includes the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

[0064] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0065] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms or by other conventional methods known to those of skill in the art.WSGR Docket No. 20012-705.601Overview of the Technology

[0066] The present disclosure provides a radiopharmaceutical that targets the carbonic anhydrase 9 (CA9) protein and can be used for therapeutic and diagnostic applications. More than 95 percent of ccRCC patients have overexpression of this protein at the tumor site. The compounds disclosed herein comprises a core of benzo[ ]thiazole-2-sulfonamide or thiazolo[4,5-c]pyridine-2-sulfonamide. Additional side chains are added to the core. In some embodiments, the additional side chains do not comprise a metal chelator. In some embodiments, one or more of the additional side chains comprise a metal chelator. In some embodiments, the metal chelator chelates a radionuclide. In some embodiments, the radiopharmaceuticals disclosed herein can detect and treat related metastases.

[0067] The first aspect of the present disclosure is a compound of Formula I:Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:G is N or CR10; each R1is independently H, halogen, -CF3, -CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -NR2R3, -C(O)NR2R3, -NR2C(NH)NR2R3, -S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O- Ci-C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein the Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R2is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, -(Ci-Ce alkyl)-(Ce-Cio aryl), -(Ci-Cs heteroalkyl)-(Ce- C10 aryl), -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl), -(Ci-Cs heteroalkyl)-(5- to 10- membered heteroaryl), -(Ci-Ce alkyl)-(3- to 10-membered heterocycloalkyl), -(Ci-Cs heteroalkyl)-(3- to 10-membered heterocycloalkyl), or 3- to 10-membered heterocycloalkyl, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substitutedWSGR Docket No. 20012-705.601 by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R3is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), or -C(0)0-(C6-Cio aryl), wherein the Ci-C6alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; orR2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Rlb; each R4is independently H, deuterium, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each Q is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -S-, -S(O)-, -S(O)2- -C(R5)=C(R5)-, — C=C— , an amino acid or a derivative thereof, Ce-Cio arylene, 5- to 10- membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R5is independently H, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or an albumin-binding moiety, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, wherein each the albuminbinding moiety is independently selected from the group consisting of:WSGR Docket No. 20012-705.601wherein * indicates a point of attachment; each R6is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), -C(0)0-(C6-Cio aryl), or the albuminbinding moiety described above, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;R10is independently H, D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ci-Ce heteroalkyl, -NR2R3, CN or NCh, wherein each C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4 alkyl)2 or CN, or R10is R1; each Rlais independently deuterium, halogen, -CN, -OH, -OCH3, C1-C4 haloalkyl, - OS(O)(Ci-C4alkyl), -OS(0)(C6-Cio aryl),-(CH2)kC(O)OH, -(CH2)kC(O)O(Ci-C4alkyl), - (CH2)kC(O)(Ci-C4 alkyl), or -NR2R3, or two Rla, together with the atoms to which they are attached, form a 4- to 6-membered heterocylyl, wherein each C1-C4 alkyl, Ce-Cio aryl, or 4- to 6- membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4alkyl)2or CN; each Rlbis independently deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH, oxo, -C(O)NR2R3, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, or -NR2R3, where each the C1-C4 alkyl, C1-C4 haloalkyl, C1-C4WSGR Docket No. 20012-705.601 alkoxy, or C1-C4 haloalkoxy is optionally substituted by 1 or 2 OH, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3; each Rlcis independently deuterium, halogen, -CN, -C(O)OH, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) OCi- C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) C1-C4 alkyl, C1-C4 haloalkoxy, -OH, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4 alkyl)kNR2C(NH)NR2R3, or -NR2R3, where each the C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is optionally substituted by 1 or 2 -OH, halogen, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3; each k is independently 0, 1, 2, or 3; each m is independently an integer from 2 to 25; each n is independently 1, 2, or 3;Y is H, R1, or -LL-Z;LL is a bond or a divalent linker connecting Q and Z; andZ is (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye.

[0068] In some embodiments, Y is hydrogen. In some embodiments, Y is halogen. In some embodiments, Y is -LL-Z. In some embodiments, when Y is -LL-Z, LL is -E-(J)P-; E is a bond, carbon, nitrogen, or a 3- to 14-membered ring system; J is independently a bond, -CR5R5- , -C(O)-, -NR6-, -O-, -O-CH2-CH2-, -CH2-O-CH2-, -CH2-CH2-O-, -S-, -S(O)-, -S(O)2-, -C(R5)=C(R5)-, — C=C— , an amino acid or derivative thereof, Ce-Cio arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein the C3- C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; and p is an integer from 2 to 25. In some embodiments, Y is -LL-Z, halogen, -CF3, -CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -C(O)NR2R3, -NR2C(NH)NR2R3, -S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein the Ci-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl isWSGR Docket No. 20012-705.601 optionally substituted by 1, 2, 3 or 4 Rlc. In some embodiments, Y is -LL-Z, halogen, -CF3, - CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl ,-C(O)NR2R3, -NR2C(NH)NR2R3, -S(O)NR2R3, -S(O)2NR2R3, wherein the Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc. In some embodiments, Y is -LL-Z, halogen, -CF3, - CN, Ci-C8alkyl, C(O)NR2R3, -NR2C(NH)NR2R3, -S(O)NR2R3, or -S(O)2NR2R3, wherein the Ci-Cs alkyl is optionally substituted by 1, 2, 3 or 4 Rla. In some embodiments, Y is -LL-Z, halogen, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb; wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc.

[0069] The second aspect of the present disclosure is a compound of Formula II:Formula II or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:G is N or CR10; each R1is independently H, halogen, -CF3, -CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -NR2R3, -C(O)NR2R3, -NR2C(NH)NR2R3, -S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O- Ci-C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein the Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R2is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, -(Ci-Ce alkyl)-(Ce-Cio aryl), -(Ci-Cs heteroalkyl)-(Ce- C10 aryl), -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl), -(Ci-Cs heteroalkyl)-(5- to 10-WSGR Docket No. 20012-705.601 membered heteroaryl), -(Ci-Ce alkyl)-(3- to 10-membered heterocycloalkyl), -(Ci-Cs heteroalkyl)-(3- to 10-membered heterocycloalkyl), or 3- to 10-membered heterocycloalkyl, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R3is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), or -C(0)0-(C6-Cio aryl), wherein the Ci-C6alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; orR2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Rlb; each R4is independently H, deuterium, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each Q is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -S-, -S(O)-, -S(O)2- -C(R5)=C(R5)-, — C=C— , an amino acid or a derivative thereof, Ce-Cio arylene, 5- to 10- membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R5is independently H, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or an albumin-binding moiety, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, wherein each the albuminbinding moiety is independently selected from the group consisting of:WSGR Docket No. 20012-705.601wherein * indicates a point of attachment; each R6is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), -C(0)0-(C6-Cio aryl), or the albuminbinding moiety described above, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;R10is independently H, D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ci-Ce heteroalkyl, -NR2R3, CN or NCh, wherein each C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4 alkyl)2 or CN, or R10is R1; each Rlais independently deuterium, halogen, -CN, -OH, -OCH3, C1-C4 haloalkyl, - OS(O)(Ci-C4alkyl), -OS(0)(C6-Cio aryl),-(CH2)kC(O)OH, -(CH2)kC(O)O(Ci-C4alkyl), - (CH2)kC(O)(Ci-C4 alkyl), or -NR2R3, or two Rla, together with the atoms to which they are attached, form a 4- to 6-membered heterocylyl, wherein each C1-C4 alkyl, Ce-Cio aryl, or 4- to 6- membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4alkyl)2or CN; each Rlbis independently deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH, oxo, -C(O)NR2R3, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, or -NR2R3, where each the C1-C4 alkyl, C1-C4 haloalkyl, C1-C4WSGR Docket No. 20012-705.601 alkoxy, or C1-C4 haloalkoxy is optionally substituted by 1 or 2 OH, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3; each Rlcis independently deuterium, halogen, -CN, -C(O)OH, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) OCi- C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) C1-C4 alkyl, C1-C4 haloalkoxy, -OH, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4 alkyl)kNR2C(NH)NR2R3, or -NR2R3, where each the C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is optionally substituted by 1 or 2 -OH, halogen, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3;E is a bond, carbon, nitrogen, or a 3- to 14-membered ring system;J is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -O-CH2-CH2-, -CH2-O- CH2-, -CH2-CH2-O-, -S-, -S(O)-, -S(O)2-, -C(R5)=C(R5)-, -C=C-, an amino acid or derivative thereof, Ce-Cio arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each k is independently 0, 1, or 2; each m is independently an integer from 2 to 25; each n is independently 1, 2, or 3; p is an integer from 2 to 25; q is 2, 3, or 4; andZ is (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye.

[0070] For both the first aspect and the second aspect, and various formulas as described herein (e.g., Formula III, Formula IV), the following embodiments apply unless indicated otherwise. In some embodiments, R1is independently halogen, -CF3, -CN, Ci-C8alkyl, C2-C8 alkenyl, Ci-C8alkoxy, -C(O)NR2R3, -NR2C(NH)NR2R3, -N(CI-C8alkyl)R3, -N(CI-C8alkyl)(C(O)O(Ci-C6alkyl), -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein the C1-C4 alkyl, Ci-C8alkyl, C2-C8alkenyl, or Ci-C8alkoxy is optionally substituted by 1, 2, 3 or 4 Rla. In some embodiments, R1is selected from the group consisting of -H, halo, - CF3, -CN, Ci-C8alkyl, Ci-C8alkenyl, Ci-C8alkoxy, -NR2R3, -NR2C(NH)NR2R3, -O-C1-C4WSGR Docket No. 20012-705.601 alkyl,cycloalkyl, 3- to 10- membered heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl, wherein each of C3- C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3, or 4 Rla, Rlb, or Rlc. In some embodiments, R1is -NR2C(=O)R2. In some embodiments, R1is -NR2C(=O)R3. In some embodiments, R1is - NR2C(=O)OR2. In some embodiments, R1is -NR2C(=O)OR3. In some embodiments, R1is halo, carboxyl, cyclooctylamino, pyridinyl, thiophenyl, thiazolyl, furanyl, imidazolyl, cyclopropyl, cyclobutyl, indazolyl, indolizinyl, pyrolyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl,independently selected from the group consisting of -H, halo, CN-, carboxyl, alkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, and phenyl. In some embodiments, each of R2, R3, and R4is independently selected from the group consisting of -H, Ci-Cs alkyl, and Ci-Cs alkyl-O-C(O)-. In some embodiments, G is CH. In some embodiments, R1is independently halogen, -CF3, -CN, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, imidazole, phenyl, pyridine, pyrazine, pyridazine, pyrimidine, pyridazin-3(2H)-one, indole,WSGR Docket No. 20012-705.601 naphthalene, benzo[d]isoxazole, benzofd] oxazole, benzo[d]isothiazole, benzo[d]imidazole, benzo[d][l,3]dioxole, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, pyrrolo[2,3-b]pyridine, indazole, quinazoline, 1,5-naphthyridine, 1,8-naphthyridine,, wherein the thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, imidazole, phenyl, pyridine, pyrazine, pyridazine, pyrimidine, pyridazin-3(2H)-one, indole, naphthalene, benzo[d]isoxazole, benzo[d]oxazole, benzo[d]isothiazole, benzo[d]imidazole, benzo[d][l,3]dioxole, imidazo[l,5- a]pyridine, pyrazolo[l,5-a]pyridine, pyrrolo[2,3-b]pyridine, indazole, quinazoline, 1,5- naphthyridine, or 1,8-naphthyridine is optionally substituted by 1, 2, 3 or 4 Rlc. In some embodiments, G is H. In some embodiments, R1is independently halogen, -CF3, -CN, C3-C8 cycloalkyl, Cs-Cs cycloalkenyl, oxetane, tetraphy drofuran, tetrahydro-2H-pyran, 3,6-dihydro- 2H-pyran, azetidine, pyrrolidine, piperidine, imidazolidine, piperazine, hexahydropyrimidine, hexahydropyridazine, oxazolidine, morpholine, 1,3-oxazinane, or 1, 2-oxazinane, wherein the C3-C8 cycloalkyl, C5-C8 cycloalkenyl, oxetane, tetraphy drofuran, tetrahydro-2H-pyran, 3,6- dihydro-2H-pyran, azetidine, pyrrolidine, piperidine, imidazolidine, piperazine, hexahydropyrimidine, hexahydropyridazine, oxazolidine, morpholine, 1,3-oxazinane, or 1, 2- oxazinane is optionally substituted by 1, 2, 3 or 4 Rlb. In some embodiments, G is H. In someWSGR Docket No. 20012-705.601towards Q, wherein # indicates connection towards Z, wherein each of e and d is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8, and wherein f is independently 1, 2, 3, 4, 5, 6, 7 or 8, with the proviso that at least one of e and d within the same bracket is not 0. In some embodiments, -E-is an integer from 1 to 25, wherein $ indicates connection towards Q, wherein # indicates connection towards Z, whereinis Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C14 cycloalkyl, C5-C14 cycloalkenyl, or 3- to 14-membered heterocycloalkyl, wherein said C3-C14 cycloalkyl, C5-C14 cycloalkenyl, or 3- to 14-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, and wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc. In some embodiments, (i) Z is the metal chelator; and (ii) the metal chelator is: AAZTA, BAT, BAT-TM, Crown, Cyclen, CB-Cyclam, DO2A, CB-DO2A,DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA-3py, PA-DOTA,WSGR Docket No. 20012-705.601DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-lpy, DOTAMAP, DOT AGA, DOT AG A- anhydride, DOTMA, DOTASA, DOTAM, DOTP, p-SCN-Bn-DOTA, DOTPA, DOTMP, DOTPM, DTP A, CHX-A"-DTPA, p-NH2-Bn-CHX-A"-DTPA, p-SCN-Bn-DTPA, p-SCN-Bz- Mx-DTPA, 1B4M-DTPA, p-SCN-BnlB-DTPA, p-SCN-Bn-lB4M-DTPA, p-SCN-Bn-CHX- A"-DTPA, CHX-A"-EDTA, MeO-DOTA-NCS EDTA, HEHA, HEHA-NCS, p-SCN-Bn- HEHA, NOTA, NOTP, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, PEPA, p-SCN- Bn-PEPA, TETPA, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, EEL1, EEL4, EEazapa, EEdecapa, bispa2, ELpypa, ELoctapa, FLCHXoctapa, p-SCN-Bn-ELoctapa, p-SCN-Bn-ELoctapa, TTHA, p-NO2-Bn-neunpa, ELoctox, EEmacropa, EEbispa2, ELphospa, Efcphospa, p-SCN-Bn-H6phospa, TETA, p-NO2-Bn-TETA, TRAP, TP A, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis- thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1 A1P, 3P-C-NETA-NCS, 3p- C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycuplAlB, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn- TCMC, motexafin, NTA, NOC, 3p-C- NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA-NCS, NODASA, NETA- monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO- BAC, DiP-LICAM, EC, SB AD, BAPEN, TACHPYR, NEC-SP, Lpy, or EuK-106, or a derivative thereof. See Scheme 2 for examples of metal chelators. In some embodiments, (i) Z is the metal chelator; and (ii) the metalWSGR Docket No. 20012-705.601salt thereof, wherein X indicates a point of attachment. In some embodiments, (i) Z is the metal chelator; and (ii) the metal chelator is the metal chelator is DOTA or a derivative thereof. In some embodiments, Z is selected from the group consisting ofDOTA, DOTA-lPy, DOTA-2Py, DOTA-3Py, DOTA-GA, DOTA-4AMP, PA-DOTA,DOTAMAP, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, DOTMP, DOTPA,WSGR Docket No. 20012-705.601 p-SCVN-Bn-DOTA, MeO-DOTA-NCS, HEHA, HEHA-NCS, NOTA, NODAGA, NOTP, NOTMP, TE2A, CB-TE2A, TE2P, CB-TE2P, CB-TE1 A1P- MM-TE2A, DM-TE2A, TETA, TETPA, p-NO2-Bn-TETA, p-NH2-Bn-TE3A, PEPA, p-SCN-Bn-PEPA, HBED, SHBED, HBED-CC, and (HBED-CC)TFP. In some embodiments, Z is HBED, NOTA, or DOTA. In some embodiments, the radionuclide is62Cu,64Cu,67Cu,68Ga, 89Zr,90Y, "mTc,105Rh,i nIn,134Ce,148Gd,149Tb,152Tb,153Pm,167Tm,175Yb,177Lu,209Bi,212Pb, 213Po,213Bi,223Ra,223Fr,227Th,225Ac, or229Th. In some embodiments, for each compound disclosed, the radionuclide is72As,134Ce,55Co,58gCo,61Cu,64Cu,66Ga,67Ga,mIn,132La,133La,177Lu,52Mn,43Sc,44Sc,153Sm,83Sr,152Tb, "mTc,45Ti,86Y, or89Zr. In some embodiments, for each compound disclosed, the radionuclide is225Ac,211At,199Au,212Bi,213Bi,67Cu,166Ho,177Lu,212Pb,223Ra,186Re,188Re,105Rh,47Sc,153Sm,161Tb,149Tb,227Th or90Y. In some embodiments, radionuclide is selected from the group consisting of225Ac,209Bi,213Bi,134Ce,62Cu,64Cu,67Cu,223Fr,68Ga,148Gd,i nIn,177LU,212Pb,213Po,153Pm,223Ra,105Rh,149Tb,152Tb, "mTc,167Tm,227Th,229Th,90Y,175Yb, and89Zr. In some embodiments, radionuclide is177Lu,90Y,225Ac,68Ga, or64Cu. In some embodiments, Z is the fluorophore. In some embodiments, Z is the dye. In some embodiments, modified pentamethine, heptamethine, ATTO 665, macrocycle, DyLight derivative, Alexa Fluor derivative, BODIPY, metallic quantum dot, CdTe-QDs, ZW800-1, IR800, IR820, ICG, 800CW, metallic nanocluster, silver nanocluster, HypoxyFluor, dicyanomethylene-4H-pyran, or Merocyanine. In some embodiments, Q is -O-Ci-Cio alkylene- or Ci-Cio alkylene. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In some embodiments, E issome embodiments, each of R11, R12, and R13is independently selected from the group consisting of -H, C1-C4 alkyl, aminoCi-C4 alkyl, -C1-C4 alkylene-S-Ci-C4 alkyl, alkylthioalkyl,phenyl, benzyl, imidazolyl, alkylimidazole, or0. In some embodiments, J is selected from the group consisting of a bond, -O-, -C(=O)-, -CH2-, -NH-, - NHC(O)-, -NHC(O)-CI-C4alkylene-, -Ci-C8alkylene-NH-, -(CH2)2-O-(CH2)2-NH-, and - (CH2)3-O-(CH2)2-NH-. In some embodiments, p is an integer from 1 to 25. In some embodiments, p is an integer from 2 to 25. In some embodiments, p is an integer from 1 to 10. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is 1. In someWSGR Docket No. 20012-705.601 embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10. In some embodiments, p is 11. In some embodiments, p is 12. In some embodiments, p is 13. In some embodiments, p is 14. In some embodiments, p is 15. In some embodiments, p is 16. In some embodiments, p is 17. In some embodiments, p is 18. In some embodiments, p is 19. In some embodiments, p is 20. In some embodiments, p is 21. In some embodiments, p is 22. In some embodiments, p is 23. In some embodiments, p is 24. In some embodiments, p is 25. In someembodiments, linker as described herein (e.g., in Formulas I, II, III, etc.) is selected from the group consisting of:WSGR Docket No. 20012-705.601WSGR Docket No 20012-705 601mbodiments, linker-HQ)— m E-(JH p - some embodiments, Z is HBED, NOTA, or DOTA; and linker isIn some embodiments, the compound comprises a structure in Table 1 to Table 16, or a derivative thereof.

[0071] A third aspect of the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.WSGR Docket No. 20012-705.601

[0072] In some embodiments, the pharmaceutical composition further comprises one or more stabilizing agent.

[0073] A fourth aspect of the present disclosure provides a method of treating a disease or disorder in a subject, the method comprising: administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition disclosed herein.

[0074] In some embodiments, the disease or disorder is cancer, and wherein the cancer is selected from the group consisting of clear-cell renal cell carcinoma, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head & neck cancer, oral cancer, and kidney cancer. In some embodiments, the cancer is clear-cell renal cell carcinoma. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is associated with carbonic anhydrase IX (CA9) overexpression in a tissue of the subject. In some embodiments, the compound is any one of those disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.

[0075] A fifth aspect of the present disclosure provides a method of optical imaging or diagnostic imaging of a biological tissue that expresses carbonic anhydrase IX (CA9), the method comprising: (a) contacting the biological tissue of a subject with a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein; and (b) detecting an optical signal indicative of cells that overexpress CA9 in the biological tissue.

[0076] In some embodiments, the compound is any one of those disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.

[0077] A sixth aspect of the present disclosure provides a method of imaging a tumor tissue that expresses carbonic anhydrase IX (CA9), the method comprising: (a) contacting the tumor tissue of a subject with a compound disclosed here or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed here; (b) detecting an optical signal indicative of cells that overexpress CA9 in the tumor tissue.

[0078] In some embodiments, the compound is any one of those disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.WSGR Docket No. 20012-705.601

[0079] The following embodiments apply to both the fifth aspect and the sixth aspect. In some embodiments, the method further comprises measuring a concentration of the compound accumulated in the subject. In some embodiments, the method further comprises measuring an amount of radiation emitted from the radionuclide, where the compound comprises the radionuclide.

[0080] In some embodiments, the compounds disclosed herein comprises a core of benzo[ ]thiazole-2-sulfonamide or thiazolo[4,5-c]pyridine-2-sulfonamide comprising a linker and a metal chelator with the linker connecting with both the core and the metal chelator.

[0081] In some embodiments, the core can connect with (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye via a linker. The metal chelator, the linker, and the radionuclide are described below.Metal Chelator

[0082] In some embodiments, the metal chelator is AAZTA, BAT, BAT-TM, Crown, Cyclen, CB-Cyclam, DO2A, CB-DO2A, DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, DOTA, DOTA-3py, PA-DOTA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-lpy, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, p-SCN- Bn-DOTA, DOTP A, DOTMP, DOTPM, DTP A, CHX-A"-DTPA, p-NH2-Bn-CHX-A"-DTPA, p-SCN-Bn-DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-BnlB-DTPA, p-SCN-Bn- 1B4M-DTPA, p-SCN-Bn-CHX-A"-DTPA, CHX-A"-EDTA, MeO-DOTA-NCS EDTA, HEHA, HEHA-NCS, p-SCN-Bn- HEHA, NOTA, NOTP, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, PEPA, p-SCN-Bn-PEPA, TETPA, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, H2azapa, Hsdecapa, bispa2, H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4OCtapa, p-SCN-Bn-H4OCtapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa2, H4phospa, Hsphospa, p-SCN-Bn-Hephospa, TETA, p-NO2-Bn-TETA, TRAP, TP A, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1 A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycuplAlB, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn- TCMC, motexafin, NT A, NOC, 3p-C-NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA-NCS, NODASA, NETA- monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO- BAC, DiP-LICAM, EC, SB AD, BAPEN, TACHPYR, NEC-SP, Lpy, or EuK-106, or a derivative thereof. In some embodiments, the chemical structure of the metal chelator isWSGR Docket No. 20012-705.601D0TA-3Py DOTA-GAWSGR Docket No. 20012-705.601p-SCN-Bn-DOTA MeO-DOTA-NCSWSGR Docket No. 20012-705.601DM-TE2A TETA TETPAWSGR Docket No. 20012-705.601t-Bu-calix[4]arene-teracarboxylic acid macropamacropa-NCS macropidWSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601SarAr-NCS AmBaSarWSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601EuK-106 , or a derivative thereof. The attachment points on these metal chelators for the linkers can take many forms. For example, if the chelator comprises multiple carboxylic acid groups, one of the carboxylic acid groups can be used to connect with the linker, such as, for example, an amine group on the linker. If an amino group is on the metal chelator, that amino group can react with a carboxylic acid group or its derivatives to form an amide bond, thereby connecting with the inker. In addition, an isothiocyanate (NCS) group on the metal chelator can reaction with a primary amine on the linker, thereby forming a thiourea and connecting with the liner. Further, a linker can be attached to the backbone of the chelator via a point of attachment (e.g., on a carbon or a hetero atom on the side chain of the chelator). Other methods are possible. In some embodiments, the chelator is DOTA or its derivatives.

[0083] Some examples of the point of attachment on a chelator can be found below:WSGR Docket No. 20012-705.601indicates a point of attachment. These are for demonstrative purposes and are not limiting. Other attachment points are possible.LinkerWSGR Docket No. 20012-705.601

[0084] In some embodiments, the compounds disclosed herein comprises a linker covalently linking the core of benzo[ ]thiazole-2-sulfonamide or thiazolo[4,5-c]pyridine-2-sulfonamide with the metal chelator. Diverse chemical structures can be used to build the linker. By changing a linker’s chemical structure, its physio-chemical characters can be modified such that the desired in vivo characters (i.e. absorption, distribution, metabolism, and excretion of the drug molecules) can be achieved. In some embodiments, the physio-chemical characters of the compound disclosed herein can be modified by changing the linker’s structure. For example, adding a PEG unit to the linker to increase hydrophilicity of the linker and the solubility of the compound comprising the linker.

[0085] In some embodiments, the linker comprises one or more groups selected from the group consisting of substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted amino acid, substituted or unsubstituted alkoxylene, substituted or unsubstituted amino, substituted or unsubstituted amino acid, -C(O)-, -C(O)O-, -S(O)- , -S(O)2- substituted or unsubstituted alkenylene, or alkynylene.

[0086] In some embodiments, , the linker comprises a structure of-(LL)n-, wherein each L is independently amino acid, -O-, -CHRX-, -C(RX)2-, -NRX-, -S-, -S(O)-, -S(O)2- =CH- - C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NRX-, -NRXC(O) -, -OC(O)NRX-, - NRXC(O)O-, -NRXC(O)NRX-, -CRX=N-, -N=CRX-, -NRXS(O)2-, -S(=O)2NRX-, - C(O)NRXS(O)2-, -S(O)2NRXC(O)-, substituted or unsubstituted Ci-Cs alkylene, substituted or unsubstituted C2-C8 alkenylene, substituted or unsubstituted C2-C8 alkynylene, substituted or unsubstituted C1-C10 heteroalkylene, -(C1-C10 alkylene)-O-, -O-(Ci-Cs alkylene)-, -(Ci-Cs alkylene)-NRx-, -NRX-(CI-C8 alkylene)-, or a click chemistry residue; and each Rxis independently a bond, hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is an integer of 1-25.

[0087] In some embodiments, the linker comprises a click chemistry residue. The linker can be attached to the core, to the metal chelator, or both via click chemistry, thereby forming one or more click chemistry residues. For example, the core can have a side chain comprising an azide group that reacts with an alkyne moiety on the linker reagent. For another example, the core can comprise an alkyne group that reacts with an azide on the linker. The metal chelator and the linker can be attached similarly by using a pair of click chemistry residues. In someWSGR Docket No. 20012-705.601 embodiments, the linker reagent comprises an azide moiety, an alkyne moiety, or both, before forming the linker between the core and the metal chelator. In some embodiments, the click chemistry residues of azide and alkyne group react with each other and form a triazole within the linker.

[0088] In some embodiments, the linker can connect with multiple moieties comprising the core of benzo[t / ]thiazole-2-sulfonamide or thiazolo[4,5-c]pyridine-2-sulfonamide. In some embodiments, the linker can connect with multiple metal chelators. Some examples of such multivalent linkers comprises the following moieties:WSGR Docket No. 20012-705.601, wherein $ indicates connection towards the core of benzo[ ]thiazole-2-sulfonamide or thiazolo[4,5-c]pyridine-2-sulfonamide, wherein # indicates connection towards metal chelator, or vice versa, wherein each of e and d is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8, and wherein f is independently 1, 2, 3, 4, 5, 6, 7 or 8, with the proviso that at least one of e and d within the same bracket is not 0. In someembodiments, the linker comprises the following moieties:connection towards the core of benzo[ ]thiazole-2-sulfonamide or thiazolo[4,5-c]pyridine-2- sulfonamide, wherein # indicates connection towards metal chelator, or vice versa, whereinis Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C14 cycloalkyl, C5-C14 cycloalkenyl, or 3- to 14-membered heterocycloalkyl, wherein said C3-C14 cycloalkyl, C5-C14 cycloalkenyl, or 3- to 14-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, and wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, as disclose elsewhere in this disclosure. The linker can comprise other moieties that provide multivalent connections to the either the core of benzo[ ]thiazole-2-sulfonamide or thiazolo[4,5- c]pyridine-2-sulfonamide or the metal chelator.

[0089] In some embodiments, in various formulas (e.g., Formulas (I), (II)) as described herein, E is a bond, carbon, nitrogen, 3- to 14-membered ring system, or a linker as described herein. In some embodiments, E is a linker, wherein the linker is a five-way linker. In some embodiments,E is a linker, wherein the linker is a four-way linker (some embodiments,WSGR Docket No. 20012-705.601E is a linker, wherein the linker is a three-way linker (embodiments, E is a linker, wherein the linker is a two-way linker.Radionuclide

[0090] In some embodiments, the compounds disclosed here comprising a metal chelator complexed with a radionuclide. In some embodiments, the compounds disclosed herein comprise a radionuclide. In some embodiments, the radionuclides include, but are not limited to, astatine-211, astatine-217, actinium-225, americium- 243, radium-223, lead-212, lead-203, copper-64, copper-67, copper-60, copper-61, copper-62, bismuth-212, bismuth-213, gallium-68, gallium-67, dysprosium- 154, gadolinium- 148, gadolinium- 153, samarium-146, samarium-147, samarium-153, terbium-149, thorium-227, thorium-229, iron-59, yttrium-86, indium-i l l, holmium- 166, technetium-94, technetium-99m, yttrium-90, lutetium- 177, terbium-161, rhenium - 186, rhenium-188, cobalt-55, scandium-43, scandium-44, scandium-47, dysprosium- 166, fluorine- 18, or iodine- 131.

[0091] In some embodiments, the type of radionuclide used in a therapeutic radiopharmaceutical can be tailored to the specific type of cancer. Radionuclides that undergo a-decay produce particles composed of neutrons and protons, and radionuclides that undergo P-decay emit energetic electrons from their nuclei. Some radionuclides can also emit Auger. In some embodiments, the compounds disclosed herein comprises an alpha particle-emitting radionuclide. Alpha radiation can cause direct, irreparable double-strand deoxynucleic acid (DNA) breaks when compared with gamma and beta radiation. Gamma and beta radiation can cause single- stranded DNA breaks via indirect DNA damage. The range of these particles in tissue and the half-life of the radionuclide can also be considered in designing the radiopharmaceutical compounds disclosed herein.

[0092] In some embodiments, a compound described herein comprises one or more independent radionuclides. In some embodiments, the compound comprises two radionuclides. In some embodiments, each of the one or more radionuclides is bound to a metal chelator of the compound. In some embodiments, two radionuclides of a compound are bound to the same metal chelator. In some embodiments, two radionuclides of a compound are bound to two independent metal chelators. In some embodiments, each of the one or more radionuclides is an alpha particle-emitting radionuclide.

[0093] In some embodiments, a compound described herein comprises an alpha particleemitting radionuclide. In some embodiments, the alpha particle-emitting radionuclide isWSGR Docket No. 20012-705.601 actinium-225 (225Ac), astatine-211 (211At), radium-223 (223Ra), radium-224 (224Ra), bismuth-213 (213Bi), Terbium-149 (149Tb), or thorium-227 (227Th). In some embodiments, the alpha particleemitting radionuclide is225Ac. In some embodiments, the alpha particle-emitting radionuclide is213Bi. In some embodiments, the alpha particle-emitting radionuclide is212Bi. In some embodiments, the alpha particle-emitting radionuclide is212Pb. In some embodiments, the alpha particle-emitting radionuclide is224Ra. In some embodiments, the alpha particle-emitting radionuclide is223Ra. In some embodiments, the alpha particle-emitting radionuclide is227Th. In some embodiments, the alpha particle-emitting radionuclide is211At. In some embodiments, the alpha particle-emitting radionuclide is149Tb. In some embodiments, the radionuclide is Zirconium-89 (89Zr). In some embodiments, a compound described herein comprises a radionuclide selected from67Cu,64Cu,89Zr,90Y,109Pd,i nAg,149Pm,153Sm,166Ho, "mTc,67Ga,68Ga,n iIn,90Y,177LU,186Re,188Re,197Au,198Au,199Au,105Rh,165Ho,161Tb,149Pm,44Sc,47Sc,70As,71As,72As,73As,74As,76As,77As,212Pb,212Bi,213Bi,225Ac,117mSn,67Ga,2O1T1,123I,131I,160Gd,148Nd,89Sr, and211At. In some embodiments, the radionuclide is225Ac. In some embodiments, the radionuclide is a decay daughter of225Ac such as221Fr,217At,213Bi,213Po,2O9T1,209Pb, or209Bi. In some embodiments, the radionuclide is177Lu. In some embodiments, the radionuclide is no-carrier added (n.c.a.)177Lu. In some embodiments, the radionuclide is nocarrier added (n.c.a.)225Ac. In some embodiments, the radionuclide is177Lu free of long-lived radioactive contaminants and byproducts. In some embodiments, the radionuclide is a non- carrier-added radionuclide. In some embodiment, positron emitters, such as, for example,18F or124I, or gamma emitters, such as, for example, "mTc,i nIn or123I, are used for diagnostic application, such as positron emission tomography (PET). In some embodiments, beta emitters, such as, for example89Sr,131I, or177Lu, are used for therapeutic applications. In some embodiments, alpha emitters, such as, for example,211At,225Ac or223Ra, are used for therapeutic applications.

[0094] In some embodiments, the alpha particle-emitting radionuclide is carrier added225Ac. In some embodiments,225Ac is generated from a heavier radionuclide. In some embodiments,225Ac is generated using a Thorium-229 generator. In some embodiments,225Ac is generated via229Th decay to225Ra from which225Ra and225Ac are then separated via ionic exchange resins. In some embodiments,229Th is generated by legacy233U stock provided by government sources. In some embodiments,225Ac is generated using Electron Linear Accelerators (LINAC) with radium-226 as a target source. In some embodiments,225Ac is be generated by the226Ra(y, n)225Ra reaction using an electron linear accelerator, and subsequent separation and purification of225Ra and225Ac using a series of ionic exchange resins. In some embodiments,225Ac is generated using a cyclical proton accelerator using radium-226 as a target source. In some embodiments,225Ac isWSGR Docket No. 20012-705.601 generated by the226Ra(p, 2n)225Ac reaction using a low energy cyclical proton accelerator (aka cyclotron). In some embodiments,225Ac is generated by the226Ra(p, 2n)225Ac reaction using a low energy cyclical proton accelerator (aka cyclotron) having an energy range between 10- 20MeV. In some embodiments,225Ac is generated using electron beam accelerators (rhodotron) using radium-226 as a target source. In some embodiments,225Ac is generated by the226Ra(y, n)225Ra reaction using an electron beam accelerator, and subsequent separation and purification of225Ra and225Ac using a series of ionic exchange resins. In some embodiments,225Ac is generated using high energy proton spallation using thorium-232 as a target source. In some embodiments,225Ac is generated using by the232Th(p, nxp)225Ac reaction using a 70-100 MeV+ high energy proton accelerator.

[0095] In some embodiments, the compound disclosed herein comprises an alpha particleemitting radionuclide bound to the metal chelator. In some embodiments, the alpha particleemitting radionuclide is actinium-225, astatine-21 1, thorium-227, or radium-223. In some embodiments, the alpha particle-emitting radionuclide is actinium-225.

[0096] In some embodiments, the compound disclosed herein comprises72As,134Ce,55Co,58gCo,61Cu,64Cu,66Ga,67Ga,n iIn,132La,133La,177Lu,52Mn,43Sc,44Sc,153Sm,83Sr,152Tb, "mTc,45Ti,86Y, or89Zr. In some embodiments, the compound comprising the above radionuclides is used for imaging, including optical imaging, diagnostic imaging, or imaging a tumor tissue that expresses carbonic anhydrase IX (CA9).

[0097] In some embodiments, the compound disclosed herein comprises225Ac,211At,199Au,212Bi,213Bi,67Cu,166HO,177LU,212Pb,223Ra,186Re,188Re,105Rh,47Sc,153Sm,161Tb,149Tb,227Th or90Y. In some embodiments, the compound comprising the above radionuclides is used for treating a disease or disorder in a subject. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is a cancer is selected from the group consisting of clear-cell renal cell carcinoma, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head & neck cancer, oral cancer, and kidney cancer. In some embodiments, the cancer is clear-cell renal cell carcinoma. In some embodiments, the disease or disorder is inflammation. In some embodiments, the disease or disorder is associated with carbonic anhydrase IX (CA9) overexpression in a tissue of the subject.Pharmaceutical Compositions

[0098] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound of Formula I or Formula II, or a stereoisomer, tautomer, hydrate,WSGR Docket No. 20012-705.601 solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0099] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed., Easton, Pa.: Mack Publishing Company (1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975); Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed., Lippincott Williams & Wilkins (1999), herein incorporated by reference for such disclosure.

[0100] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formula I or Formula II with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0101] The pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations,WSGR Docket No. 20012-705.601 extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0102] All formulations for oral administration are in dosages suitable for such administration. Examples of such dosage units are tablets or capsules. In some embodiments, these contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and typically from about 5 to 150 mg. A suitable daily dose for a human or other mammal vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods and practices.

[0103] The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine (e.g., as therapeutic or diagnostic compositions). The pharmaceutical carrier, excipient or diluent can be selected based on the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), stabilizing agent(s), preservative(s), or dye(s). Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985), herein incorporated by reference for such disclosure.

[0104] Conventional formulation techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.Stabilizing Agents

[0105] In some embodiments, the disclosed pharmaceutical composition may comprise one or more stabilizing agents. The stabilizing agent can comprise (i) a radiolysis stabilizer, which can be an amino acid or a peptide or a derivative thereof; (ii) a vitamin or a derivative thereof, (iii) a lipid or a derivative thereof, (iv) a carbohydrate or a derivative thereof, (v) a volume expander, (vi) an antioxidant, a free metal chelator, or a pH stabilizer.

[0106] In some embodiments, the amino acid or peptide used as a stabilizing agent is selected from N-acetyl-L-cysteine, glutathione, L-Lysine, selenol-L-methionine, glutathione, albumin, melatonin, taurine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and derivatives thereof.WSGR Docket No. 20012-705.601

[0107] In some embodiments, the radiolysis stabilizer is an antioxidant, such as a flavonoid or a derivative thereof. In some embodiments, the flavonoid is (2S,3R)-2-(3,4-dihydroxyphenyl)- 3,4-dihydro-l(2H)-benzopyran-3,5,7-triol 3 -(3,4,5-trihydroxybenzoate ((-) catechin gallate or CG), 3,3’,4’,5,5’,7-hexahydroxy flavylium chloride, (-)-cis-3,3’,4’,5,7-pentahydroxyflavane (epi -catechin or EC), 7-Hydroxy-3-(4’-methoxyphenyl)-4H-b enzopyran-4-one, 3,4,5- trihydroxybenzoic acid (gallic acid), 3,4’,5,7-tetrahydroxyflavone (Kaempferol), Luteolin, 2- (3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy- [[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl oxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4- one (rutin hydrate), Quercetin, [(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3,4-dihydro- 2H-l-benzopyran-3-yl]3,4,5-trihydroxybenzoate or epicatechin gallate (ECG), or (2R,3S)-2- (3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (Gallo-Catechin or GC).

[0108] In some embodiments, the flavonoid is a catechin or a derivative thereof, for example, (2S,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-l(2H)-benzopyran-3,5,7-triol 3-(3,4,5- trihydroxybenzoate ((-)catechin gallate or CG), (-)-cis-3,3,4’,5,7-pentahydroxyflavane (epicatechin or EC), 3,4,5-trihydroxybenzoic acid (gallic acid), [(2R,3 R)-5,7-dihydroxy-2-(3,4,5- trihydroxyphenyl)-3,4-dihydro-2H-l-benzopyran-3-yl]3,4,5-trihydroxybenzoate (epigallo- catechin gallate or EGCg), epi-catechin gallate ECG, (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4- dihydro-2H-chromene-3,5,7-triol (epigallo-catechin or EGC), or gallo-catechin or GC.

[0109] In some embodiments, the antioxidant can also be a carotenoid or a derivative thereof, such as all-trans-fucoxanthin, lycopene, xanthophyll, beta carotene, lycopene, or lutein. In some embodiments, the antioxidant is N-acetyl cysteine, L-ascorbic acid, N-tert-butyl-a- phenylnitrone, dihydroxyphenyl)-2-propenoic acid (caffeic acid), P-carotene, provitamin A, catechin gallate or CG, 1, 4, 5-trihydroxy cyclohexanecarboxylic acid, trans-4-hydroxy cinnamic acid (p-coumaric acid), 3,3’,4’,5,5’,7-hexahydroxyflavylium chloride, thiocytic acid (dihydrolipoic ccid, DHLA), 4,4’,5,5’,6,6’-hexahydroxydiphenic acid 2, 6, 2’, 6’ -dilactone (Ellagic acid), (-)-cis -3,3’,4’,5,7-pentahydroxyflavane (epi-catechin or EC), 2-methoxy-4-(2- propenyl) phenol, trans-4-hydroxy-3 -methoxy cinnamic acid (Ferulic acid), 7-hydroxy-3-(4’- methoxyphenyl)-4H-benzopyran-4-one, all-trans-Fucoxanthin, 3,4,5-trihydroxybenzoic acid (gallic acid), (-)-gallo-catechin, glutathione, Kaempferol, (±)-l,2-dithiolane-3 -pentanoic acid, luteolin, lycopene, L-lysine, neochlorogenic acid, oleic acid, trans-3,5,4’-Trihydroxystilbene (Resveratrol), 2-(3,4-di hydroxyphenyl)-5,7-dihydroxy-3-[(2 S,3R,4 S,5S,6R)-3,4,5-tri hydroxy-6- [(2R, 3R, 4R, 5R,6 S)-3,4,5-tri hydroxy-6-methyl oxan-2-yl]oxymethyl]oxan-2- yl]oxychromen-4-one, rutin hydrate, selenol-L-methionine, thiourea, (+)-a-tocopherol, xanthophyll, citric acid (CA), gentisic acid (GA), salicylic acid (SA), erythorbic acid (EA), phenol, sodium bisulfite, butylated hydroxy anisole, butylated hydroxy toluene, metabisulfite,WSGR Docket No. 20012-705.601 benzyl alcohol, thymol, lipoic acid (LA), thioglycolic acid (TGA), 2,3 -dimercaptopropan- l-ol (BAL), zinc, selenium, albumin, ethanol, mannitol, sucrose, melatonin, ebselen, pyruvic acid, carboxy-PTIO, trolox, uric acid, edaravone, beta carotene, NADPH, Lycopene, lutein, catalase, estrogen, estradiol, estriol, ubiquinol , copper, quercetin, cortisone, taurine, epi-catechin gallate (ECG), epigallo-catechin or EGC, (2R,3S)-2-(3,4,5-tri hydroxyphenyl)-3,4-dihydro-2H- chromene-3,5,7-triol (gallo-catechin or GC), (-)-epigalocatechin-3-O-gallate, 5-aminolevulibic acid hydrate, polysorbate 80, garlic acid, sodium L-ascorbate, hyaluronic acid, dextran 60-90, selenol, and LysaKare. In some embodiments, the radiolysis stabilizer can also be a vitamin or a derivative thereof, for example, L-ascorbic acid, P-carotene, provitamin A, (+)-a-tocopherol, erythorbic acid (EA), trolox, or lutein.

[0110] In some embodiments, the radiolysis stabilizer is a lipid. The lipid can be a fatty acid, such as a saturated or unsaturated Ce to C30 fatty acid. In some embodiments, the fatty acid is oleic acid, myristoleic acid, palmitoleic acid, sapienic acid, elaidic acid, vaccenic acid, linoleic acid, or a-linolenic acid. In another embodiment, the lipid is a steroid or derivatives thereof, for example, estrogen, estradiol, estriol, or cortisone.

[0111] In some embodiments, the radiolysis stabilizer is a carbohydrate or a derivative thereof, such as mannitol, sucrose, dextran (e.g., dextran 40, dextran 70), and cyclodextrins, (e.g., alphacyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin). In some embodiments, the radiolysis stabilizer is a volume expander. The volume expander can be a polymer or a polymer mixture, such as PEG 3350, PEG 4000, polygeline, haemaccel, gelofusine, and PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride and potassium chloride US FDA 2018 Label).

[0112] In some embodiments, the volume expander is selected from dextran, dextran 40, dextran 70, cyclodextrins, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, PEG 3350, PEG 4000, polygeline, gelofusine, and PLENVU (polyethylene glycol 3350, sodium sulfate, ascorbic acid, sodium chloride and potassium chloride US FDA 2018 Label).

[0113] In some embodiments, the pharmaceutical composition of the present disclosure comprises a free metal chelator, which is not attached to the compounds disclosed here. In some embodiments, the free metal chelator is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTP A), 2-S-(4-isothiocyanatobenzyl)-l,4,7- triazacyclononane-l,4,7-triacetic acid (NOTA), tri ethylenetetramine (TETA), 1 , 4, 7, 10, 13- pentaazacyclopentadecane-N, N’, N”, N’”, N” ’’-pentaacetic acid (PEPA), 1,4,8, 11- teiraazacyclo tetradecane-1,4,8, 11-t.etrapropionic acid (TETPA), triethylenetetraminepentaaceiic acid, 2,2’ ,2”-(l 0-(2,6-dioxotetrahydro-2H-pyran-3-yl)-l ,4,7, 10-tetraazacyclododecane- 1 ,4,7- iriyljtri acetic acid (DOTA-GA), 1 ,4,7, 10-tetraazacyclododecane-l ,4,7,10~tetra(m ethyleneWSGR Docket No. 20012-705.601 phosphonic acid (DOTP), deferoxamine (DFO), N,N-bis(2-hydroxybenzyl)ethy1enediaraine-N,N-diacetic aci d (HBED), 1,4, 7, 10-tetraazacyclododecane- 1 ,4, 7, 10-tetra(methy lene phosphonic acid) (DOTP), 6,6 -(( 1 ,4, 10, 13 -tetraoxa-7, 16-diazacy clooctadecane-7, 16- diyl)bis(methy1ene))-dipicolinic acid (Macropa), meso-2,3-dimercaptosuccinic acid (DMSA), dimercaptopropane sulfonate (DMPS), dihydrolipoic acid (DHLA), lipoic acid (LA), thiogly colic acid (TGA), and 2,3 dimercaptopropan- 1 -ol (BAL). In some embodiments, the free metal chelator is EDTA. In some embodiments, the free metal chelator is D I PA. In some embodiments, the free metal chelator is Macropa. In some embodiments, the free metal chelator is present in the pharmaceutical composition from about 0.001 wt% to about 10 wt%. In some embodiments, the free metal chelator is present in the pharmaceutical composition from aboutO.01 wt% to about 5.0 wt.%, from about 0.05 wt% to about 2.5 wt%, or from about 0.10 wt% to about 1.0 wt / o. In some embodiments, the free metal chelator is present in the pharmaceutical composition at a concentration of from about 0.01 mg / mL to about 50 mg / mL, from about 0.05 mg / mL to about 25 mg / mL, or from about 0. 1 mg / mL to about 5 mg / mL . hi some embodiments, the free metal chelator is present in the pharmaceutical composition from about 10 iiiM to about 500 mM, from about 20 mM to about 250 mM, or from about 50 m.M to about 100 mM.

[0114] In some embodiments, the pharmaceutical composition comprises a pH stabilizer. In some embodiments, the pH stabilizer is the same as the radiolysis stabilizer. In some embodiments, the pH stabilizer comprises an organic acid, such as, for example, acetic acid, fumaric acid, ascorbic acid, propionic acid, benzene sulfonic acid, carbonic acid, citrate acid, aspartic acid, maleic acid, methane sulfonic acid, or tartaric acid. In some embodiments, the pH stabilizer comprises an inorganic acid, such as, for example, hydrobromic acid, hydrochloric acid, phosphoric acid, boric acid, or sulfuric acid. In some embodiments, the pH stabilizer comprises a base, such as, for example, tromethamine (Tris), ammonium hydroxide, diethanolamine, or sodium hydroxide. In some embodiments, the pH stabilizer comprises an amino acid or a salt thereof. In some embodiments, the pH stabilizer comprises sodium acetate, sodium ascorbate, ascorbic acid, acetic acid, fumaric acid, propionic acid, ascorbic acid, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzene sulfonic acid, sodium benzoate, sodium bicarbonate, boric acid, sodium carbonate, carbonic acid, diethanolamine, citrate acid, hydrobromic acid, glycine, histidine, sodium lactate, lysine, maleic acid, methane sulfonic acid, phosphate acid, monobasic sodium phosphate acid, tribasic sodium phosphate acid, dibasic sodium phosphate acid, sodium hydroxide, sodium / di sodium succinate, sulfuric acid, sodium tartrate, tartaric acid, tromethamine, or a combination thereof. In some embodiments, the one or more pH stabilizers are present in the pharmaceutical compositionWSGR Docket No. 20012-705.601 from about 0.001 wt% to about 10 wt%. from about 0.01 wt% to about 5.0%, or from about 0.1 wt% to about 2.0%. In some embodiments, the pH stabilizer is present in the pharmaceutical composition at about 0.01 wt% to about 5 vvt%, about 0.05 wt% to about 2 wt%, or about 0. 1 wt% to about 1 wt%. In some embodiments, the pH stabilizers is present in the pharmaceutical composition at a concentration from about 0.1 to about 5.0 mg / rnL, from about 0.2 mg / rnL to about 2.5 mg / mL, or from 0.5 mg / mL to about 1.5 mg / mL. In some embodiments, the pH stabilizer is present in the pharmaceutical composition from about 10 mM to about 500 mM, from about 20 mM to about 250 mM, or from 40 mM to about 125 mM. The pH stabilizer can be configured to maintain a pH of the pharmaceutical composition from about 4.0 to about 8.0, from about 5.0 to about 7.0, or from 5.5 to about 6.5. The pH stabilizer can be configured to maintain a pH value of the pharmaceutical composition within a range from about 5.0 to about 7.0. In some embodiments, the pH of the pharmaceutical composition is within a range from about 4.0 to about 8.0. In some embodiments, the pH of the pharmaceutical composition is within a range from about 5.5 to about 6.0.Radiolabeling Methods

[0115] In one aspect, the present disclosure provides methods of radiolabeling a compound as described herein. In some embodiments, radiolabeling of a compound as described herein comprises a step of complexing a chelator with a radionuclide as described herein. The present disclosure recognizes that many radiolabeled products comprise labile functional groups that do not withstand conventional reaction conditions, e.g., elevated temperature, and long reaction time. When labile functional groups are lost under a radiolabeling condition, a side-product is generated. The generation of side-products presents a challenge to the efficient preparation and purification of radiolabeled products and greatly limits the utility of many existing radiolabeling methods. The radiolabeling methods as described herein provide unexpected benefits for preparing radiopharmaceuticals. For example, radiolabeling methods as described herein provide fewer side-products. In some embodiments, a side-product is a deprotected product of the intended radiolabeled product. In some embodiments, a side-product is a de-Boc product of the intended radiolabeled product. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 20%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 15%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 10%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 9%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than aboutWSGR Docket No. 20012-705.6018%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 7%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 6%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 5%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 4%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 3%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 2%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 1.8%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 1.5%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 1.3%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 1%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 0.8%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 0.5%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 0.2%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 0.1%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 0.05%. In some embodiments, a side-product is generated under a radiolabeling condition in an amount of no greater than about 0.01%.

[0116] The present disclosure provides an insight that, among other parameters, pH, temperature, and / or reaction time affects the generation of a side-product in radiolabeling reactions. In some embodiments, a radiolabeling method is carried out in the presence of a pH buffer. In some embodiments, a pH buffer comprises sodium acetate. In some embodiments, a pH buffer is a sodium acetate buffer. In some embodiments, a radiolabeling method is carried out in a pH from about 4.5 to about 6.5. In some embodiments, a radiolabeling method is carried out in a pH from about 5.0 to about 6.0. In some embodiments, a radiolabeling method is carried out in a pH from about 5.2 to about 5.8. In some embodiments, a radiolabeling method is carried out in a pH from about 5.4 to about 5.6. In some embodiments, a radiolabeling method is carried out in a pH from about 5.2 to about 5.5. In some embodiments, a radiolabeling method is carried out in a pH of about 5.45. In some embodiments, a radiolabeling method is carried out in a pH greater than about 4.0. In some embodiments, a radiolabeling method is carried out in a pH lower than about 7.0.WSGR Docket No. 20012-705.601

[0117] In some embodiments, a radiolabeling method is carried out at a temperature from about -20 °C to about 200 °C. In some embodiments, a radiolabeling method is carried out at a temperature from about -20 °C to about 0 °C. In some embodiments, a radiolabeling method is carried out at a temperature from about 0 °C to about 25 °C. In some embodiments, a radiolabeling method is carried out at a temperature from about 40 °C to about 150 °C. In some embodiments, a radiolabeling method is carried out at a temperature from about 50 °C to about120 °C. In some embodiments, a radiolabeling method is carried out at a temperature from about 60 °C to about 100 °C. In some embodiments, a radiolabeling method is carried out at a temperature from about 70 °C to about 90 °C. In some embodiments, a radiolabeling method is carried out at a temperature of about 70 °C. In some embodiments, a radiolabeling method is carried out at a temperature of about 80 °C. In some embodiments, a radiolabeling method is carried out at a temperature of about 90 °C.

[0118] In some embodiments, a radiolabeling method is carried out for at least about 5 min. In some embodiments, a radiolabeling method is carried out for at least about 10 min. In some embodiments, a radiolabeling method is carried out for at least about 15 min. In some embodiments, a radiolabeling method is carried out for at least about 20 min. In some embodiments, a radiolabeling method is carried out for at least about 30 min. In some embodiments, a radiolabeling method is carried out for at least about 1 hour. In some embodiments, a radiolabeling method is carried out for at least about 2 hours. In some embodiments, a radiolabeling method is carried out for at least about 3 hours. In some embodiments, a radiolabeling method is carried out for at least about 5 hours. In some embodiments, a radiolabeling method is carried out for about 5 min. In some embodiments, a radiolabeling method is carried out for about 10 min. In some embodiments, a radiolabeling method is carried out for about 15 min. In some embodiments, a radiolabeling method is carried out for about 20 min. In some embodiments, a radiolabeling method is carried out for about 30 min. In some embodiments, a radiolabeling method is carried out for about 1 hour. In some embodiments, a radiolabeling method is carried out for about 2 hours. In some embodiments, a radiolabeling method is carried out for about 3 hours. In some embodiments, a radiolabeling method is carried out for about 5 hours.Therapeutic Methods

[0119] In one aspect, the present disclosure provides methods of treating a disease or condition in a subject in need thereof. The methods can comprise administering a pharmaceutical composition comprising a compound disclosed herein to the subject in need thereof. TheWSGR Docket No. 20012-705.601 methods can provide a therapeutic and / or prophylactic benefit to a subject in need thereof, the method comprising administering a pharmaceutical composition described herein.

[0120] The methods can comprise administering to a subject a pharmaceutical composition that comprise a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject has cancer. In some embodiments, the cancer is a clear cell renal cell carcinoma (ccRCC). In some embodiment, the methods comprising compound uptake and on-target residence time up to seven days after the administration. In some embodiments, the radiopharmaceuticals disclosed herein can treat other CA9-presenting cancers, such as, for example, non-small cell lung cancer, pancreatic cancer, bladder cancer, breast cancer, ovarian cancer, prostate cancer, and head and neck cancer.

[0121] In some embodiment, the subject has hypoxia-related diseases, such as, for example, breast cancer, pancreatic cancer, colon cancer, multidrug resistant colon cancer, rectal cancer, colorectal cancer, metastatic colorectal cancer, lung cancer, non-small cell lung cancer, head and neck cancer, ovarian cancer, hypopharynx cancer, nasopharynx cancer, larynx cancer, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, glioma, astrocytoma, cervix cancer and kidney cancer.

[0122] The present disclosure provides methods of visualizing and treating a disease, condition, or disorder in an animal by delivering a radioisotope to tumors or tissues expressing carbonic anhydrase 9. The methods generally comprise the step of administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a patient in need thereof to treat the disorder or disease. In certain embodiments, the present disclosure provides a use of a compound as described herein in the manufacture of a medicament for visualizing or treating a disease, condition, or disorder by delivering a radioisotope to a tumor.Embodiments

[0123] Embodiment 1. A compound of Formula I:Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:G is N or CR10;WSGR Docket No. 20012-705.601 each R1is independently H, halogen, -CF3, -CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -NR2R3, -C(O)NR2R3, -NR2C(NH)NR2R3, -S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O- Ci-C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein the Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R2is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, -(Ci-Ce alkyl)-(Ce-Cio aryl), -(Ci-Cs heteroalkyl)-(Ce- C10 aryl), -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl), -(Ci-Cs heteroalkyl)-(5- to 10- membered heteroaryl), -(Ci-Ce alkyl)-(3- to 10-membered heterocycloalkyl), -(Ci-Cs heteroalkyl)-(3- to 10-membered heterocycloalkyl), or 3- to 10-membered heterocycloalkyl, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R3is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), or -C(0)0-(C6-Cio aryl), wherein the Ci-C6alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; orR2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Rlb; each R4is independently H, deuterium, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;WSGR Docket No. 20012-705.601 each Q is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -S-, -S(O)-, -S(O)2- -C(R5)=C(R5)-, — C=C— , an amino acid or a derivative thereof, Ce-Cio arylene, 5- to 10- membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R5is independently H, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or an albumin-binding moiety, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, wherein each the albuminbinding moiety is independently selected from the group consisting of:wherein * indicates a point of attachment; each R6is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), -C(0)0-(C6-Cio aryl), or the albuminbinding moiety described above, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;R10is independently H, D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ci-Ce heteroalkyl, -NR2R3, CN or NO2, wherein each C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted by one or more halogen,WSGR Docket No. 20012-705.601OH, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(CI-C4 alkyl), N(CI-C4 alkyl)2 or CN, or R10is R1; each Rlais independently deuterium, halogen, -CN, -OH, -OCH3, C1-C4 haloalkyl, - OS(O)(Ci-C4alkyl), -OS(0)(C6-Cio aryl),-(CH2)kC(O)OH, -(CH2)kC(O)O(Ci-C4alkyl), - (CH2)kC(O)(Ci-C4 alkyl), or -NR2R3, or two Rla, together with the atoms to which they are attached, form a 4- to 6-membered heterocylyl, wherein each C1-C4 alkyl, Ce-Cio aryl, or 4- to 6- membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(CI-C4 alkyl), N(CI-C4alkyl)2or CN; each Rlbis independently deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH, oxo, -C(O)NR2R3, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, or -NR2R3, where each the C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy is optionally substituted by 1 or 2 OH, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3; each Rlcis independently deuterium, halogen, -CN, -C(O)OH, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) OCi- C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) C1-C4 alkyl, C1-C4 haloalkoxy, -OH, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4 alkyl)kNR2C(NH)NR2R3, or -NR2R3, where each the C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is optionally substituted by 1 or 2 -OH, halogen, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3; each k is independently 0, 1, 2, or 3; each m is independently an integer from 2 to 25; each n is independently 1, 2, or 3;Y is H, R1, or -LL-Z;LL is a bond or a divalent linker connecting Q and Z; andZ is (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye.

[0124] Embodiment 2. The compound of Embodiment 1, wherein Y is H.

[0125] Embodiment 3. The compound of Embodiment 1, wherein Y is halogen.

[0126] Embodiment 4. The compound of Embodiment 1, wherein Y is -LL-Z.

[0127] Embodiment 5. The compound of Embodiment 4, wherein:LL is -E-(J)P-;WSGR Docket No. 20012-705.601E is a bond, carbon, nitrogen, or a 3- to 14-membered ring system;J is independently a bond,CH2-, -CH2-CH2-O-, -S-, -S(O)-, -S(O)2-, -C(R5)=C(R5)-, -C=C-, an amino acid or derivative thereof, Ce-Cio arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; and p is an integer from 2 to 25.

[0128] Embodiment 6. A compound of Formula II:Formula II or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:G is N or CR10; each R1is independently H, halogen, -CF3, -CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -NR2R3, -C(O)NR2R3, -NR2C(NH)NR2R3, -S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O- Ci-C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein the Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R2is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, -(Ci-Ce alkyl)-(Ce-Cio aryl), -(Ci-Cs heteroalkyl)-(Ce- C10 aryl), -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl), -(Ci-Cs heteroalkyl)-(5- to 10- membered heteroaryl), -(Ci-Ce alkyl)-(3- to 10-membered heterocycloalkyl), -(Ci-Cs heteroalkyl)-(3- to 10-membered heterocycloalkyl), or 3- to 10-membered heterocycloalkyl, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;WSGR Docket No. 20012-705.601 each R3is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), or -C(0)0-(C6-Cio aryl), wherein the Ci-C6alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; orR2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Rlb; each R4is independently H, deuterium, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each Q is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -S-, -S(O)-, -S(O)2- -C(R5)=C(R5)-, — C=C— , an amino acid or a derivative thereof, Ce-Cio arylene, 5- to 10- membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R5is independently H, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or an albumin-binding moiety, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, wherein each the albuminbinding moiety is independently selected from the group consisting of:WSGR Docket No. 20012-705.601wherein * indicates a point of attachment; each R6is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), -C(0)0-(C6-Cio aryl), or the albuminbinding moiety described above, wherein the Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;R10is independently H, D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ci-Ce heteroalkyl, -NR2R3, CN or NCh, wherein each C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4 alkyl)2 or CN, or R10is R1; each Rlais independently deuterium, halogen, -CN, -OH, -OCH3, C1-C4 haloalkyl, - OS(O)(Ci-C4alkyl), -OS(0)(C6-Cio aryl),-(CH2)kC(O)OH, -(CH2)kC(O)O(Ci-C4alkyl), - (CH2)kC(O)(Ci-C4 alkyl), or -NR2R3, or two Rla, together with the atoms to which they are attached, form a 4- to 6-membered heterocylyl, wherein each C1-C4 alkyl, Ce-Cio aryl, or 4- to 6- membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4alkyl)2or CN; each Rlbis independently deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH, oxo, -C(O)NR2R3, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, or -NR2R3, where each the C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy is optionally substituted by 1 or 2 OH, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3; each Rlcis independently deuterium, halogen, -CN, -C(O)OH, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) OCi- C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) C1-C4 alkyl, C1-C4 haloalkoxy,WSGR Docket No. 20012-705.601-OH, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4alkyl -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, or -NR2R3, where each the Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, Ci-C4haloalkoxy, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is optionally substituted by 1 or 2 -OH, halogen, Ci-C2alkoxy, Ci-C2haloalkoxy, or -NR2R3;E is a bond, carbon, nitrogen, or a 3- to 14-membered ring system;J is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -O-CH2-CH2-, -CH2-O- CH2-, -CH2-CH2-O-, -S-, -S(O)-, -S(O)2-, -C(R5)=C(R5)-, -C=C-, an amino acid or derivative thereof, Ce-Cio arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein the C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein the Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each k is independently 0, 1, or 2; each m is independently an integer from 2 to 25; each n is independently 1, 2, or 3; p is an integer from 2 to 25; q is 2, 3, or 4; andZ is (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye.

[0129] Embodiment 7. The compound of any one of Embodiments 1-6, wherein R1is independently halogen, -CF3, -CN, Ci-C8alkyl, C2-C8alkenyl, Ci-C8alkoxy, -C(O)NR2R3, - NR2C(NH)NR2R3, -N(CI-C8alkyl)R3, -N(CI-C8alkyl)(C(O)O(Ci-C6alkyl), -(O-Ci-C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-Ci-C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein the Ci-C4alkyl, Ci-C8alkyl, C2-C8alkenyl, or Ci-C8alkoxy is optionally substituted by 1, 2, 3 or 4 Rla.

[0130] Embodiment 8. The compound of Embodiment 7, wherein G is CH.

[0131] Embodiment 9. The compound of any one of Embodiments 1-6, wherein R1is independently halogen, -CF3, -CN, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, imidazole, phenyl, pyridine, pyrazine, pyridazine, pyrimidine, pyridazin-3(2H)-one, indole, naphthalene, benzo[d]isoxazole, benzo[d] oxazole, benzo[d]isothiazole, benzo[d]imidazole, benzo[d][l,3]dioxole, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, pyrrolo[2,3-b]pyridine, indazole, quinazoline, 1,5-naphthyridine, 1,8-naphthyridine,, wherein the thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, imidazole, phenyl, pyridine, pyrazine,WSGR Docket No. 20012-705.601 pyridazine, pyrimidine, pyridazin-3(2H)-one, indole, naphthalene, benzo[d]isoxazole, benzo[d]oxazole, benzo[d]isothiazole, benzo[d]imidazole, benzo[d][l,3]dioxole, imidazo[l,5- a]pyridine, pyrazolo[l,5-a]pyridine, pyrrolo[2,3-b]pyridine, indazole, quinazoline, 1,5- naphthyridine, or 1,8-naphthyridine is optionally substituted by 1, 2, 3 or 4 Rlc.

[0132] Embodiment 10. The compound of Embodiment 9, wherein G is CH.

[0133] Embodiment 11. The compound of any one of Embodiments 1-6, wherein R1is independently halogen, -CF3, -CN, C3-C8 cycloalkyl, Cs-Cs cycloalkenyl, oxetane, tetraphydrofuran, tetrahydro-2H-pyran, 3,6-dihydro-2H-pyran, azetidine, pyrrolidine, piperidine, imidazolidine, piperazine, hexahydropyrimidine, hexahydropyridazine, oxazolidine, morpholine, 1,3-oxazinane, or 1, 2-oxazinane, wherein the C3-C8 cycloalkyl, C5-C8 cycloalkenyl, oxetane, tetraphydrofuran, tetrahydro-2H-pyran, 3,6-dihydro-2H-pyran, azetidine, pyrrolidine, piperidine, imidazolidine, piperazine, hexahydropyrimidine, hexahydropyridazine, oxazolidine, morpholine, 1,3-oxazinane, or 1, 2-oxazinane is optionally substituted by 1, 2, 3 or 4 Rlb.

[0134] Embodiment 12. The compound of Embodiment 11, wherein G is CH.

[0135] Embodiment 13. The compound of any one of Embodiments 6-12, wherein -E-WSGR Docket No. 20012-705.601, wherein $ indicates connection towards Q, wherein # indicates connection towards Z, wherein each of e and d is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8, and wherein f is independently 1, 2, 3, 4, 5, 6, 7 or 8, with the proviso that at least one of e and d within the same bracket is not 0.

[0136] Embodiment 14. The compound of any one of Embodiments 6-12, wherein -E-is an integer from 1 to 25, wherein $ indicates connection towards Q, wherein # indicates connection towards Z, whereinis Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C14 cycloalkyl, C5-C14 cycloalkenyl, or 3- to 14-membered heterocycloalkyl, wherein the C3-C14 cycloalkyl, C5-C14 cycloalkenyl, or 3- to 14-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, and wherein the Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc.WSGR Docket No. 20012-705.601

[0137] Embodiment 15. The compound of any one of Embodiments 1 or 4-14, wherein (i) Z is the metal chelator; and (ii) the metal chelator is: AAZTA, BAT, BAT-TM, Crown, Cyclen, CB-Cyclam, DO2A, CB-DO2A, DO3 A, H3HP-DO3 A, Oxo-DO3 A, p-NH2- Bn-Oxo-DO3 A, DOTA, DOTA-3py, DOTA-PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-lpy, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, p-SCN- Bn-DOTA, DOTP A, DOTMP, DOTPM, DTP A, CHX-A"-DTPA, p-NH2-Bn-CHX-A"-DTPA, p-SCN-DTPA, p-SCN-Bz-Mx-DTPA, 1B4M-DTPA, p-SCN-BnlB-DTPA, p-SCN-Bn-lB4M- DTPA, p-SCN-Bn-CHX-A"-DTPA, CHX-A"-EDTA, MeO-DOTA-NCS EDTA, HEHA, HEHA-NCS, p-SCN-Bn- HEHA, NOTA, NOTP, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, PEPA, p-SCN-Bn-PEPA, TETPA, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, H2azapa, Hsdecapa, bispa2, H4pypa, H4octapa, H4CHXoctapa, p-SCN-Bn-H4OCtapa, p-SCN-Bn-H4OCtapa, TTHA, p-NO2-Bn-neunpa, H4octox, H2macropa, H2bispa2, H4phospa, Hsphospa, p-SCN-Bn-Hephospa, TETA, p- NO2-Bn-TETA, TRAP, TP A, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1 A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycuplAlB, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn- TCMC, motexafin, NT A, NOC, 3p-C-NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C-NE3TA-NCS, NODASA, NETA- monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO- BAC, DiP-LICAM, EC, SB AD, BAPEN, TACHPYR, NEC-SP, Lpy, or EuK-106, or a derivative thereof.

[0138] Embodiment 16. The compound of any one of Embodiments 1 or 4-14, wherein (i)WSGR Docket No. 20012-705.601indicates a point of attachment.

[0139] Embodiment 17. The compound of any one of Embodiments 1 or 4-14, wherein (i) Z is the metal chelator; and (ii) the metal chelator is DOTA or a derivative thereof.WSGR Docket No. 20012-705.601

[0140] Embodiment 18. The compound of any one of Embodiments 1 or 4-17, wherein the radionuclide is225Ac,209Bi,213Bi,134Ce,62Cu,64Cu,67Cu,223Fr,68Ga,148Gd,U 1ln,177Lu,212Pb,213Po,153Pm,223Ra,105Rh,149Tb,152Tb, "mTc,167Tm,227Th,229Th,90Y,175Yb, or89Zr.

[0141] Embodiment 19. The compound of any one of Embodiments 1 or 4-17, wherein the radionuclide is72As,134Ce,55Co,58gCo,61Cu,64Cu,66Ga,67Ga,U 1ln,132La,133La,177Lu,52Mn,43Sc,44Sc,153Sm,83Sr,152Tb, "mTc,45Ti,86Y, or89Zr.

[0142] Embodiment 20. The compound of any one of Embodiments 1 or 4-17, wherein the radionuclide is225Ac,211At,199Au,212Bi,213Bi,67Cu,166Ho,177Lu,212Pb,223Ra,186Re,188Re,105Rh,47Sc,153Sm,161Tb,149Tb,227Th or90Y.

[0143] Embodiment 21. The compound of any one of Embodiments 1 or 4-14, wherein Z is the fluorophore.

[0144] Embodiment 22. The compound of any one of Embodiments 1 or 4-14, wherein Z is the dye.

[0145] Embodiment 23. The compound of any one of Embodiments 1 or 4-14, wherein Z is modified pentamethine, heptamethine, ATTO 665, macrocycle, DyLight derivative, Alexa Fluor derivative, BODIPY, metallic quantum dot, CdTe-QDs, ZW800-1, IR800, IR820, ICG, 800CW, metallic nanocluster, silver nanocluster, HypoxyFluor, dicyanomethylene-4H-pyran, or Merocyanine.

[0146] Embodiment 24. A compound of any one of Embodiments 1-23, wherein the compound comprises a structure in Table 1 to Table 17, or a derivative thereof.

[0147] Embodiment 25. A pharmaceutical composition comprising a compound of any one of Embodiments 1-24 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0148] Embodiment 26. The pharmaceutical composition of Embodiment 25, further comprising one or more stabilizing agent.

[0149] Embodiment 27. A method of treating a disease or disorder in a subject, the method comprising:(a) administering to the subject an effective amount of a compound of any one of Embodiments 1-24 or a pharmaceutical composition of Embodiments 25 or 26.

[0150] Embodiment 28. The method of Embodiment 27, wherein the disease or disorder is cancer, and wherein the cancer is selected from the group consisting of clear-cell renal cell carcinoma, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head & neck cancer, oral cancer, and kidney cancer.WSGR Docket No. 20012-705.601

[0151] Embodiment 29. The method of Embodiment 28, wherein the cancer is clear-cell renal cell carcinoma.

[0152] Embodiment 30. The method of Embodiment 27, wherein the disease or disorder is inflammation.

[0153] Embodiment 31. The method of Embodiment 27, wherein the disease or disorder is associated with carbonic anhydrase IX (CA9) overexpression in a tissue of the subject.

[0154] Embodiment 32. The method of any one of Embodiments 27-31, wherein the compound is any one of Embodiment 20 or Embodiment 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.

[0155] Embodiment 33. A method of optical imaging or diagnostic imaging of a biological tissue that expresses carbonic anhydrase IX (CA9), the method comprising:(a) contacting the biological tissue of a subject with a compound of any one of Embodiments 1-24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiments 25 or 26; and(b) detecting an optical signal indicative of cells that overexpress CA9 in the biological tissue.

[0156] Embodiment 34. The method of Embodiment 33, wherein the compound is any one of Embodiment 19 or Embodiment 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.

[0157] Embodiment 35. A method of imaging a tumor tissue that expresses carbonic anhydrase IX (CA9), the method comprising:(a) contacting the tumor tissue of a subject with a compound of any one of Embodiments 1-23 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiments 24 or 25; and(b) detecting an optical signal indicative of cells that overexpress CA9 in the tumor tissue.

[0158] Embodiment 36. The method of Embodiment 35, wherein the compound is any one of Embodiment 19 or Embodiment 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.

[0159] Embodiment 37. The method of any one of Embodiments 33-36, further comprising: measuring a concentration of the compound accumulated in the subject.WSGR Docket No. 20012-705.601

[0160] Embodiment 38. The method of any one of Embodiments 33-37, further comprising: measuring an amount of radiation emitted from the radionuclide, where the compound comprises the radionuclide, the fluorophore, or the dye.

[0161] Embodiment 39. The method of any one of Embodiments 33-38, wherein the detecting is conducted by positron emission tomography (PET), single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI).

[0162] Embodiment 40. The method of Embodiment 38 or Embodiment 39, further comprising: performing an imaging scan, detecting a measurable signal due to the radionuclide or the fluorophore or the dye from the subject; and generating an image from the measurable signal, thereby obtaining an image of a tissue or an organ of the subject.Methods for the Preparation of Compounds of the Formula I and II

[0163] Compounds of the Formula I and II can be prepared in accordance with synthetic methods well known to the skilled person and as described herein.

[0164] One general route to a subset of compounds of Formula I denoted by A- 5 is illustrated in Scheme A.SCHEME AA-3g: A = CO2H A-4g: A = CO2H A-5g: A = CO2H A-6g: A = CO2H(a) NBS or NIS. (b) boronic acid / boronate / terminal alkyne, base, palladium catalyst, ligand, heat or alkyl bromide / iodide, Ni catalyst, base, heat; or (CHs)6Sn2, palladium catalyst, ligand, heat; then aryl bromide / iodide,WSGR Docket No. 20012-705.601 palladium catalyst, ligand, Cui, heat, (c) Fe, NH4CI, heat, (d) R2X, CS2CO3, heat or aldehyde, STAB, DCM; then acid chloride or decarbonate, base, (e) R3=Boc: DPP A, t-BuOH, base, heat; then R2X, CS2CO3, heat, (f) t-BuLi, -78 °C; then B(OCHS)3.; then HNR2R3, Cu(OTf)2, base, heat or HNR2R3, base, Pd, ligand, heat, (g) BzNCS, then aqueous NaOH, heat; then HCl (aq), heat or S2CI2, heat, (h) CuBrpCuCb t-BuNCh- (i) NaSH, then NaClO aqueous ammonia; then MCPBA or i-PrMgCl, THF, -78 °C then t-BuONSO. (j) EtOC(S)SK, DMF, heat; then aqueous NH4OH, NaClO, NaOH, cooling; then MCPBA; (k) for (PG)2N=BOCHN: di-tert-butyl dicarbonate, base, DMAP; for (PGfN =(PMB)2N: PMB-Cl, base, heat. (I) for (PG) 2N=BocHN : HCl, heat; for (PGfN =(PMB)2N: TFA, heat.

[0165] In Scheme A, a benzo[d]thiazole-2-sulfonamide (A-5) can be prepared from an aniline (A-l) or 2-fluoroaniline (A-2). In the first case an aniline (A-l) is treated with benzoyl isocyanate in an aprotic solvent such as propane-2-one and stirred for the requisite time, occasionally with heating. The resulting thiourea is treated with aqueous sodium hydroxide in a solvent such as THF for sufficient time to cleave the benzoyl group. Heating the resulting compound in sulfur chloride, or other chlorinating agent, yields the benzo[d]thiazol-2-amine (A- 3). A-3 is converted to a 2-chlorobenzo[d]thiazole or 2-bromobenzo[d]thiazole (A-4), by diazotization in the presence of copper(II) chloride or bromide, respectively. Heating A-4 with sodium hydrosulfide in a protic solvent such as ethanol, followed by reaction with sodium chlorite in aqueous ammonia, often with cooling, affords an S-(benzo[d]thiazol-2- yl)thiohydroxylamine intermediate, which can be oxidized by MCPBA, or related reagents, to afford a benzo[d]thiazole-2-sulfonamide (A-5). Alternatively, A-4 can be converted directly to A-5 by treating the former with i-PrMgCl or related reagent at low temperature, and then trapping the anionic intermediate with tert-butoxy(sulfmylidene)amine.

[0166] Likewise, a benzo[d]thiazole-2-sulfonamide (A-5) can be prepared from a 2- fluoroaniline (A-2), by heating A-2 with potassium O-ethyl carb onodi thioate in an aprotic solvent such as DMF to afford an intermediate benzo[d]thiazole-2(3H)-thione, which can be treated with aqueous ammonia and sodium hydroxide to give an S-(benzo[d]thiazol-2- yl)thiohydroxylamine. As described above, this material can be oxidized to give a b enzo [ d] thi azol e-2- sulfonami de (A- 5 ) .

[0167] In Scheme A, substituent A can be manipulated in several ways and at any step in the process. Some examples of the manipulations include brominating or iodinating the ring by action of NBS, NIS or some other halogenating agent, typically with heating in an aprotic solvent. The halogenated intermediate can then be coupled with organic boronates, tin reagents,WSGR Docket No. 20012-705.601 nitrogen nucleophiles or halocarbons by action of palladium, copper or nickel catalysts, with suitable ligands, usually by heating in the appropriate solvent with a suitable base present. In some cases, first conversion of A from bromine / iodine to a boronate or trialkylstannane allows coupling with a halocarbon or nitrogen nucleophile. When A is a nitro group, reduction with iron or hydrogen in the presence of palladium catalysis produces a primary amine. This amine can then be alkylated sequentially, or alkylated and then reacted with an acylating, oxoacylating or aminoacylating agent. Alternatively, the steps can be reversed, and the primary amine can be first treated with the acylating agent and then alkylated. Examples in which A is an alkoxy carbonylated amine can also be prepared directly from a carboxylic acid by the action of DPPA in the presence of a suitable alcohol. In some cases, it is optimal to first protect the sulfonamide group, prior to performing the manipulations on the A substituent. In these cases, A- 5 can be converted to a Boc- or bis(PMB)-protected derivative by the action of di(t-butyl) dicarbonate or PBM-C1 and base in an aprotic solvent, respectively, often with heating. In both cases, once substituent A has been suitably modified, the sulfonamide protecting group(s) can be removed by treatment with a strong acid, such as TFA. Finally, when A=NR1R2and one of R' / R2is H and the other contains a free hydroxyl or NH group, a ring can be formed by heating the material in the presence of a carbonylating agent such as di-t-butyl dicarboxylate, carbonyl(diimidazole), triphosgene, or related reagents.

[0168] One general route to a subset of compounds of Formula I denoted by B-8 is illustrated in Scheme B.SCHEME B(a) HOCH2LCH2N(PG)2, DEAD, TPP. (b) NaSH, then NaClO aqueous ammonia; thenMCPBA or i-PrMgCl, THF, -78 °C then t-BuONSO. (c) TFA,WSGR Docket No. 20012-705.601 heat, (d) for N(PG)2=N3: Fe, aqueous NH4CI, heat; for N(PG)2=NHBoc: HCl or TFA; (e) derivatizing agent and deprotect as necessary.

[0169] In Scheme B, an N-protected linker (HOCH2LCH2N(PG)2) is prepared by multiple steps of condensing monoprotected diols, amino acid couplings, click chemistry, and other approaches well known to those skilled in the art. This linker is then coupled to a hydroxybenzo[d]thiazole (B-l, B-2 or B-3) by heating them in an aprotic solvent in the presence of DEAD or DIAD and TPP. Heating the 2-bromobenzo[d]thiazole (B-4) with sodium hydrosulfide in a protic solvent such as ethanol, followed by reaction with sodium chlorite in aqueous ammonia, often with cooling, affords an S-(benzo[d]thiazol-2-yl)thiohydroxylamine intermediate, which can be oxidized by MCPBA, or related reagents, to afford a benzo[d]thiazole-2-sulfonamide (B-5). Alternatively, B-4 can be converted directly to B-5 by treating the former with i-PrMgCl or related reagent at low temperature, and then trapping the anionic intermediate with tert- butoxy(sulfinylidene)amine. B-6 is also converted to the free sulfonamide B-5 by the action of TFA and heating. When B-5 incorporates an azide as the protected nitrogen group (i.e., N(PG)2=NS), it is converted to B-7 by a reducing agent such as iron. Conversely, when a Boc group is used (i.e., N(PG)2=NHBoc), a strong acid such as HCl or TFA effects the conversion to B-7. Finally, a metal coordinating group (Z) is introduced by a suitable reagent, often a N- hydroxysuccinimide ester, and any protected carboxylate groups are liberated.

[0170] In Scheme B, substituent A retains the same meaning as in Scheme A, and the same manipulations at any stage can be accomplished.

[0171] Another general route to a subset of compounds of Formula I denoted by C-4 is illustrated in Scheme C.(a) boronic acid / boronate (including Ar-B(OH) 2) , Pd, ligand, heat.(b) HOCH2LCH2N(PG)2, DEAD, TPP. (c) for N(PG)2=N3: Fe, aqueousWSGR Docket No. 20012-705.601NH4CI, heat; for N(PG)2=NHBOC: HCl or TFA; (d) Derivatizing agent and deprotect as necessary.

[0172] In Scheme C, an N-protected linker (HOCH2LCH2N(PG)2) is prepared by multiple steps of condensing monoprotected diols, amino acid couplings, click chemistry, and other approaches well known to those skilled in the art. A bromo- or iodo-benzo[d]thiazole-2-sulfonamide (C-l) is coupled to a phenolic boronate or boronic acid, by heating with a palladium catalyst with base in a protic or aprotic solvents to afford C-2. In some cases, the phenolic oxygen atom is protected as a silyl or glycolic ether, in which case the phenol C-2 is liberated after the coupling step by the action of fluoride or aqueous acid. The phenol (C-2) is then coupled to the side chain using a combination of a DEAD and TPP to give C-3. The protecting group of C-3 is removed and the resulting amine is converted to a metal chelator group as described in Scheme B.

[0173] One general route to a subset of compounds of Formula II denoted by D-4 is illustrated in Scheme D.SCHEME D(a) DEAD, TPP. (b) for N(PG)2=Ns: Fe, aqueous NH4CI, heat; then TFA, heat; for N(PG)2=NHBOC: TFA, heat, (c) Derivatizing agent and deprotect as necessary.

[0174] In Scheme D, an N-protected poly-alcoholic linker (D-2) is prepared by multiple steps of condensing monoprotected diols, amino acid couplings, click chemistry, and other approaches well known to those skilled in the art. A PMB-protected hydroxybenzo[d]thiazole-2- sulfonamide (D-l) is coupled with D-2 by action of DEAD and TPP in an aprotic solvent. When D-3 incorporates an azide as the protected nitrogen group (i.e., N(PG)2= , it is converted to the primary amine by a reducing agent such as iron and subsequent heating with TFA removes the PMB groups from the sulfonamide. Conversely, when a Boc group is used (i.e., N(PG)2=NHBOC), heating with TFA cleaves both Boc and PMB groups. Finally, a metalWSGR Docket No. 20012-705.601 coordinating group (Z) is introduced by a suitable reagent, often a N-hydroxysuccinimide ester, and any protected carboxylate groups are liberated.

[0175] In Scheme D, substituent A retains the same meaning as in Scheme A, and the same manipulations at any stage can be accomplished.CHEMISTRYExamplesExample 1. tert-butyl ethyl(2-sulfamoylbenzo[d1thiazol-7-yl)carbamate

[0176] Step 1 : tert-butyl N-(2-fluoro-3-nitrophenyl)carbamate. To a stirred mixture of 2-fluoro- 3 -nitroaniline (2.00 g, 12.8 mmol, 1 equiv.) and di-tert-butyl dicarbonate (27.96 g, 128 mmol, 10 equiv.) in dioxane (20 mL) at 80°C under nitrogen atmosphere. The resulting mixture was stirred for 3 days at 80 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford tert-butyl N- (2-fhioro-3-nitrophenyl)carbamate (2.50 g, 76%) as a white solid. C11H13FN2O4: MW 256. LC-MS (ESI, m / z): [M + H]+ = 257.

[0177] Step 2: tert-butyl N-ethyl-N-(2-fluoro-3-nitrophenyl)carbamate. To a stirred mixture of tert-butyl N-(2-fluoro-3-nitrophenyl)carbamate (2.5 g, 9.76 mmol, 1 equiv.) and CS2CO3 (6.36 g, 19.5 mmol, 2 equiv.) in DMF (25 mL) were added KI (324 mg, 1.95 mmol, 0.2 equiv.) and ethyl iodide (3.04 g, 19.5 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford tert-butyl N-ethyl-N-(2-fluoro-3-nitrophenyl)carbamate (2.00 g, 72%) as a white solid. C13H17FN2O4: MW 284. LC-MS (ESI, m / z): [M + H]+ = 285. 1H NMR (300 MHz, Chloroform-d) 5 7.95 (ddd, J = 8.4, 6.6, 1.8 Hz, 1H), 7.57 - 7.47 (m, 1H), 7.31 - 7.23 (m, 1H), 3.67 (q, J = 7.1 Hz, 2H), 1.41 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H).

[0178] Step 3: tert-butyl N-(3-amino-2-fluorophenyl)-N-ethylcarbamate. To a stirred mixture of tert-butyl N-ethyl-N-(2-fluoro-3-nitrophenyl)carbamate (2.00 g, 7.04 mmol, 1 equiv.) and NH4CI (1.88 g, 35.2 mmol, 5 equiv.) in EtOH (20 mL) and water (20 mL) was added iron (1.96 g, 35.2 mmol, 5 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 85 °C under nitrogen atmosphere. The desired product could be detected byWSGR Docket No. 20012-705.601LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / methanol (5: 1) to afford tert-butyl N-(3-amino-2-fluorophenyl)-N-ethylcarbamate (1.7 g, 95%) as a white solid. C13H19FN2O2: MW 254. LC-MS (ESI, m / z): [M + H]+ =255. 1H NMR (300 MHz, Chloroform-d) 5 6.89 (td, J = 8.0, 1.4 Hz, 1H), 6.69 (td, J = 8.0, 1.7 Hz, 1H), 6.57 (t, J = 3.7 Hz, 1H), 3.61 (q, J = 7.1 Hz, 2H), 1.40 (s, 9H), 1.11 (t, J = 7.1 Hz, 3H).

[0179] Step 4: tert-butyl N-ethyl-N-(2-sulfanylidene-3H-l,3-benzothiazol-7-yl)carbamate. To a stirred mixture of tert-butyl N-(3-amino-2-fluorophenyl)-N-ethylcarbamate (1.70 g, 6.69 mmol, 1 equiv.) and potassium O-ethyl carb onodi thioate (2.45 g, 20.1 mmol, 3 equiv.) in DMF (20 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford tert-butyl N-ethyl-N-(2- sulfanylidene-3H-l,3-benzothiazol-7-yl)carbamate (1 g, 48%) as a white solid. C14H18N2O2S2: MW 310. LC-MS (ESI, m / z): [M + H]+ = 311.

[0180] Step 5: tert-butyl N-[2-(aminosulfanyl)-l,3-benzothiazol-7-yl]-N-ethylcarbamate. Into a 40 mL vial were added NaClO (15 mL, 222 mmol, 23 equiv.) and aqueous ammonia (9.0 mL, 231 mmol, 24 equiv.) at -10 °C. The resulting mixture was stirred for 15 min at -10 °C under nitrogen atmosphere. To the above mixture was added tert-butyl N-ethyl-N-(2-sulfanylidene- 3H-l,3-benzothiazol-7-yl)carbamate (1.00 g, 3.22 mmol, 1 equiv.) and KOH (754 mg, 13.4 mmol, 1.4 equiv.) in portions at -10 °C. The resulting mixture was stirred for an additional 1 h at room temperature. The desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with water (3 x 3 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 60%) to afford tert-butyl N-[2- (aminosulfanyl)-l,3-benzothiazol-7-yl]-N-ethylcarbamate (1000 mg, 95%) as a brown solid. C14H19N3O2S2: MW 325. LC-MS (ESI, m / z): [M + H]+ = 326. 1H NMR (400 MHz, DMSO- d6) 5 7.65 (dd, J = 8.1, 1.1 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.19 (d, J = 7.9 Hz, 1H), 5.00 (s, 2H), 3.65 (q, J = 7.0 Hz, 2H), 1.33 (s, 9H), 1.03 (t, J = 7.0 Hz, 3H).

[0181] Step 6: tert-butyl N-ethyl-N-(2-sulfamoyl-l,3-benzothiazol-7-yl)carbamate. A mixture of tert-butyl N-[2-(aminosulfanyl)-l,3-benzothiazol-7-yl]-N-ethylcarbamate (100 mg, 0.307 mmol, 1 equiv.) and m-CPBA (212.09 mg, 1.228 mmol, 4 equiv.) in THF (3 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / methanol (9: 1) to afford tert-butyl N- ethyl-N-(2-sulfamoyl-l,3-benzothiazol-7-yl)carbamate (80 mg, 73%) as a white solid.WSGR Docket No. 20012-705.601C14H19N3O4S2: MW 357. LC-MS (ESI, m / z): [M + H]+ = 358. 1H NMR (400 MHz, DMSO- d6) 5 8.41 (s, 2H), 8.12 (dd, J = 8.3, 1.0 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.59 (dd, J = 7.7, 1.0 Hz, 1H), 3.72 (q, J = 7.1 Hz, 2H), 1.34 (s, 9H), 1.04 (t, J = 7.0 Hz, 3H).

[0182] Using the above procedure, the following examples in Table 1 were prepared.Table 1Example 3, 7-(ethylamino)benzord]thiazole-2-sulfonamide

[0183] 7-(Ethylamino)-l,3-benzothiazole-2-sulfonamide. To a stirred solution of tert-butyl N- ethyl-N-(2-sulfamoyl-l,3-benzothiazol-7-yl)carbamate (30 mg, 0.084 mmol, 1 equiv.) in DCM (1 mL) was added TFA (0.60 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.1% FA, Mobile Phase B: ACN; Flow rate: 75 mL / min; Gradient: 5% B to 5% B in 5 min; 5% B to 55% B in 0 min; 55% B to 65% B in 15 min; 65% B to 95% B in 5 min; Detector, 254 / 220 nm) to afford 7-(ethylamino)-WSGR Docket No. 20012-705.601 l,3-benzothiazole-2-sulfonamide (19 mg, 89%) as a yellow solid. C9H11N3O2S2: MW 257.LC-MS (ESI, m / z): [M + H]+ = 258. 1H NMR (400 MHz, DMSO-d6) 5 8.27 (s, 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.38 (dd, J = 8.2, 1.0 Hz, 1H), 6.70 (dd, J = 7.9, 1.0 Hz, 1H), 6.12 (t, J = 5.4 Hz, 1H), 3.25 (qd, J = 7.1, 5.3 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H).Using the above procedure, the following examples in Table 2 were prepared.Table 2Example 5, 7-(Cvclooctylamino)benzord1thiazole-2-sulfonamide

[0184] Step 1 : 7-Bromo-3H-l,3-benzothiazole-2-thione. A solution of 3-bromo-2-fluoroaniline (2.50 g, 13.2 mmol, 1 equiv.) and ethoxy(potassiosulfanyl) methanethione (4.64 g, 28.9 mmol, 2.2 equiv.) in DMF (15 mL) was stirred for 16 hours at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with cold water (150 mL). The mixture was acidified with HC1 (10 mL, 2.0 mol / L). The precipitated solids were collected by filtration and washed with DCM (3 x 5 mL). This resulted in 7-bromo-3H-l,3-benzothiazole-2-thione (2.15 g, 66%) as an off-white solid. C7H4BrNS2: MW 246. LC-MS (ESI, m / z): [M - H]- = 244, 246. 1H NMR (400WSGR Docket No. 20012-705.601MHz, DMSO-d6) 5 7.51 (dd, J = 7.8, 1.1 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.30 (dd, J = 8.1, 1.1 Hz, 1H).

[0185] Step 2: [(7-Bromo-l,3-benzothiazol-2-yl)sulfanyl]amine. To a stirred mixture of aqueous ammonia (22 mL, 25%) and NaClO (11.5 mL) were added a solution of 7-bromo-3H-l,3- benzothiazole-2-thione (2.00 g, 8.13 mmol, 1 equiv.) and NaOH (390 mg, 9.75 mmol, 1.2 equiv., dissolved in 5.5 mL H2O) at -10°C under nitrogen atmosphere. The resulting mixture was stirred for one hour at 0 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with cold water (30 mL). This resulted in [(7-bromo-l,3-benzothiazol-2- yl)sulfanyl]amine (1.80 g, 85%) as a white solid. C7H5BrN2S2: MW 261. LC-MS (ESI, m / z): [M + H]+ = 261, 263. 1H NMR (400 MHz, DMSO-d6) 5 7.74 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 5.09 (s, 2H).

[0186] Step 3: 7-Bromo-l,3-benzothiazole-2-sulfonamide. To a stirred solution of 7-bromo-l,3- benzothiazole-2-sulfonamide (1.80 g, 6.14 mmol, 1 equiv.) in THF (20 mL) was added mCPBA (4.76 g, 27.6 mmol, 4 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 15% ethyl acetate in dichloromethane to afford 7-bromo-l,3-benzothiazole-2-sulfonamide (750 mg, 37%) as a white solid. C7H5BrN2O2S2: MW 293. LC-MS (ESI, m / z): [M + H]+ = 293, 295.

[0187] Step 4: tert-butyl N-(7 -bromo- l,3-benzothiazol-2-ylsulfonyl)carbamate. To a stirred solution of 7-bromo-l,3-benzothiazole-2-sulfonamide (700 mg, 2.388 mmol, 1 equiv.) and TEA (724.90 mg, 7.164 mmol, 3.0 equiv.) in THF (7.0 mL) were added di-tert-butyl dicarbonate (1.04 g, 4.78 mmol, 2 equiv.) and DMAP (29 mg, 0.24 mmol, 0.1 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions (Cl 8, 120g; Mobile Phase A: Water / 0.1% FA, Mobile Phase B: ACN; Flow rate: 65mL / min; Gradient: 5% B to 5% B in 4 min, 5% B to 40% B in 1 min, 45% B to 95% B in 30 min; Detector, 254 / 220 nm) to afford tert-butyl N-(7-bromo-l,3-benzothiazol-2-ylsulfonyl)carbamate (670 mg, 71%) as a white solid. C12H13BrN2O4S2: MW 393. LC-MS (ESI, m / z): [M - H]- = 391, 393. 1H NMR (400 MHz, DMSO-d6) 5 8.08 (dd, J = 8.2, 0.9 Hz, 1H), 7.75 (dd, J = 7.9, 0.9 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 1.21 (s, 9H).

[0188] Step 5: tert-butyl N-[7-(cyclooctylamino)-l,3-benzothiazol-2-ylsulfonyl]carbamate. To a stirred mixture of tert-butyl N-(7-bromo-l,3-benzothiazol-2-ylsulfonyl)carbamate (620 mg,WSGR Docket No. 20012-705.6011.577 mmol, 1 equiv.), dicaesium(l+) ion carbonate (1.54 g, 4.73 mmol, 3.0 equiv.) and cyclooctanamine (401 mg, 3.15 mmol, 2.0 equiv.) in dioxane (7.0 mL) was added { l,3-bis[2,6- bis(pentan-3-yl)phenyl]-4, 5-di chi oro-2, 3-dihy dro-lH-imidazol-2-yl}di chi oro(2 -methyl- llambda4-pyridin-l-yl)palladium (133 mg, 0.158 mmol, 0.1 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions (C18, 120 g; Mobile Phase A: Water / 0.1% FA, Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 5% B to 5% B in 4 min, 5% B to 50% B in 1 min, 50% B to 95% B in 30 min; Detector, 254 / 220 nm) to afford tert-butyl N-[7-(cyclooctylamino)-l,3-benzothiazol-2- ylsulfonyl]carbamate (400 mg, 58%) as a yellow solid. C20H29N3O4S2: MW 440. LC-MS (ESI, m / z): [M + H]+ = 440. 1H NMR (400 MHz, DMSO-d6) 5 7.47 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 5.95 (s, 1H), 3.70 - 3.62 (m, 1H), 1.87 - 1.78 (m, 2H), 1.77 - 1.67 (m, 4H), 1.63 - 1.47 (m, 8H), 1.29 (s, 9H).

[0189] Step 6: 7-(Cyclooctylamino)-l,3-benzothiazole-2-sulfonamide. To a stirred solution of tert-butyl N-[7-(cyclooctylamino)-l,3-benzothiazol-2-ylsulfonyl]carbamate (200 mg, 0.455 mmol, 1 equiv.) in THF (2.0 mL) was added HC1 (2.0 mL, 1.0 mol / L in 1,4-dioxane) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 40 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30* 150mm 5pm, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 48% B to 66% B in 8 min; Wave Length: 254 / 220 nm; RT1 : 7.9 min) to afford 7-(cyclooctylamino)-l,3- benzothiazole-2-sulfonamide (63 mg, 41%) as a yellow solid. C15H21N3O2S2: MW 339. LCMS (ESI, m / z): [M + H]+ = 340. 1H NMR (400 MHz, DMSO-d6) 5 8.25 (s, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.1, 0.9 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 5.84 (d, J = 7.9 Hz, 1H), 3.70 - 3.60 (m, 1H), 1.86 - 1.78 (m, 2H), 1.77 - 1.67 (m, 4H), 1.66 - 1.44 (m, 8H).Example 6, tert-butyl ethyl(6-(3-methoxypropoxy)-2-sulfamoylbenzo[d1thiazol-7- yDcarbamate

[0190] Step 1 : 2-Bromo-l,3-benzothiazol-6-ol. A mixture of 2-bromo-6-methoxy-l,3- benzothiazole (14.5 g, 59.4 mmol, 1 equiv.) and BBr3 (1.0 M in DCM, 529 mL, 528 mmol, 8.9WSGR Docket No. 20012-705.601 equiv.) in DCM (250 mL) was stirred for 18 h at 40 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched by the addition of Water / Ice (500 mL) at 0 °C. The resulting mixture was extracted with CH2CI2 (3 x 1 L). The combined organic layers were washed with water (1 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10% - 20%) to afford 2-bromo-l,3- benzothiazol-6-ol (11.31 g, 83%) as a white solid. C7H4BrNOS: MW 230. LC-MS (ESI, m / z): [M + H]+ = 230, 232. 1H NMR (400 MHz, DMSO-d6) 5 9.98 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.8, 2.5 Hz, 1H).

[0191] Step 2: 2-Bromo-7-nitro-l,3-benzothiazol-6-ol. To a stirred mixture of 2-bromo-l,3- benzothiazol-6-ol (11.3 g, 49.1 mmol, 1 equiv.) in H2SO4 (65 mL) was added KN03 (4.97 g, 49.1 mmol, 1 equiv., dissolved in 20 mL of H2O) dropwise at -10 °C. The resulting mixture was stirred for 3 h at room temperature. The desired product could be detected by LCMS. The resulting mixture was diluted with water (500 mL) and extracted with CH2Q2 (3 x 1 L). The combined organic layers were washed with water (1 x 1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 30%) to afford 2-bromo-7-nitro- l,3-benzothiazol-6-ol (11 g, 81%) as a yellow solid. C7H3BrN2O3S: MW 275. LC-MS (ESI, m / z): [M + H]+ = 275, 277. 1H NMR (300 MHz, Chloroform-d) 5 11.17 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H).

[0192] Step 3: 2-Bromo-6-(3-methoxypropoxy)-7-nitro-l,3-benzothiazole. To a stirred mixture of 2-bromo-7-nitro-l,3-benzothiazol-6-ol (5.49 g, 20.0 mmol, 1 equiv.) and l-bromo-3- methoxypropane (6.11 g, 39.9 mmol, 2 equiv.) in DMF (25 mL) was added K2CO3 (5.52 g, 39.9 mmol, 2 equiv.) at 12 °C. The resulting mixture was stirred for 2 h at 80 °C. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluted with CH2Q2 / EA (10% - 20%) to afford 2-bromo-6-(3-methoxypropoxy)-7-nitro-l,3-benzothiazole (5.47 g, 79%) as an orange solid. Cl 1H1 lBrN2O4S: MW 347. LC-MS (ESI, m / z): [M + H]+ = 347, 349. 1H NMR (400 MHz, Chloroform-d) 5 8.16 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 9.1 Hz, 1H), 4.36 (t, J = 6.1 Hz, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.37 (s, 3H), 2.23 - 2.14 (m, 2H).

[0193] Step 4: 2-Bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7-amine. To a stirred mixture of 2-bromo-6-(3-methoxypropoxy)-7-nitro-l,3-benzothiazole (5.47 g, 15.8 mmol, 1 equiv.) in EtOH (36 mL) and water (36 mL) were added iron (4.40 g, 78.8 mmol, 5 equiv.) and NH4CI (3.37 g, 63.0 mmol, 4 equiv.) at 15 °C. The resulting mixture was stirred for 1 h at 80 °C. The desired product could be detected by LCMS. The reaction mixture was filtered and the filtrateWSGR Docket No. 20012-705.601 was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 30%) to afford 2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7- amine (4.45 g, 89%) as a white solid. Cl lH13BrN2O2S: MW 317. LC-MS (ESI, m / z): [M + H]+ = 317, 319. 1H NMR (300 MHz, Chloroform-d) 5 7.41 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 4.18 (t, J = 6.2 Hz, 2H), 3.59 (t, J = 6.1 Hz, 2H), 3.37 (s, 3H), 2.15 - 2.03 (m, 2H).

[0194] Step 5: tert-butyl N-[2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7-yl]carbamate. A mixture of 2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7-amine (4.45 g, 14.0 mmol, 1 equiv.) and di-tert-butyl dicarbonate (24.5 g, 112 mmol, 8 equiv.) in methanol (100 mL) was stirred for 16 h at 60 °C. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / EA (20% - 30%) to afford tert-butyl N-[2-bromo-6-(3- methoxypropoxy)-l,3-benzothiazol-7-yl]carbamate (4.11 g, 70%) as a white solid. C16H21BrN2O4S: MW 417. LC-MS (ESI, m / z): [M + H]+ = 417, 419. 1H NMR (400 MHz, Chloroform-d) 5 7.70 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 7.10 (d, J = 8.9 Hz, 1H), 4.22 (t, J = 6.1 Hz, 2H), 3.59 (t, J = 5.8 Hz, 2H), 3.40 (s, 3H), 2.13 - 2.03 (m, 2H), 1.56 (s, 9H).

[0195] Step 6 : tert-butyl N-[2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7-yl]-N- ethylcarbamate. A solution of tert-butyl N-[2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7- yl]carbamate (4.11 g, 9.85 mmol, 1 equiv.) in DMF (25 mL) was treated with NaH (0.350 g, 14.8 mmol, 1.5 equiv.) for 1 h at 0 °C under nitrogen atmosphere followed by the addition of iodoethane (2.30 g, 14.8 mmol, 1.5 equiv.) at 0 °C. The resulting mixture was stirred for 1 h at 10 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was quenched with water (250 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water (1 x 250 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / EA (0% - 10%) to afford tert-butyl N-[2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7-yl]-N-ethylcarbamate (3.50 g, 80%) as a colorless oil. C18H25BrN2O4S: MW 445. LC-MS (ESI, m / z): [M + H]+ = 445, 447.

[0196] Step 7: tert-butyl N-ethyl-N-[6-(3-methoxypropoxy)-2-sulfamoyl-l,3-benzothiazol-7- yl]carbamate. A solution of tert-butyl N-[2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7- yl]-N-ethylcarbamate (1.00 g, 2.25 mmol, 1 equiv.) in THF (10 mL) was treated with isopropylmagnesium chloride (2.0 M solution in THF, 1.35 mL, 2.69 mmol, 1.2 equiv.) for 30 min at -78 °C under nitrogen atmosphere followed by the addition of (tert- butoxy)(sulfinylidene)amine (364 mg, 2.69 mmol, 1.2 equiv.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 5 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with water (2 mL) at 0WSGR Docket No. 20012-705.601°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 5 min; 5% B to 30% B in 1 min; 30% B to 60% B in 30 min; 60% B to 95% B in 5 min;95% B to 95% B in 3 min; Detector, 254 / 220 nm) to afford tert-butyl N-ethyl-N-[6-(3- methoxypropoxy)-2-sulfamoyl-l,3-benzothiazol-7-yl]carbamate (90 mg, 9%) as a white solid. C18H27N3O6S2: MW 446. LC-MS (ESI, m / z): [M + H]+ = 446. 1H NMR (400 MHz, DMSO- d6) 5 8.32 (s, 2H), 8.09 (dd, J = 8.9, 3.0 Hz, 1H), 7.51 (d, J = 9.1 Hz, 1H), 4.27 - 4.13 (m, 2H), 3.78 - 3.62 (m, 1H), 3.55 - 3.39 (m, 3H), 3.24 (s, 3H), 2.03 - 1.92 (m, 2H), 1.49 (s, 3H), 1.22 (s, 6H), 1.03 (dt, J = 26.6, 7.1 Hz, 3H).Example 7, 7-bromo-5-(3-methoxypropoxy)benzo[d1thiazole-2-sulfonamide

[0197] Step 1 : l-Bromo-3-(3-methoxypropoxy)-5-nitrobenzene. A mixture of 3-bromo-5- nitrophenol (20 g, 91.741 mmol, 1 equiv.) and l-bromo-3-methoxypropane (14.46 g, 94.5 mmol, 1.03 equiv.) in ACN (250 mL) were added CS2CO3 (59.78 g, 183 mmol, 2 equiv.) and KI (1.52 g, 9.17 mmol, 0.1 equiv.) at room temperature. The resulting mixture was stirred for overnight at 60 °C. Desired product could be detected by TLC (PE / EA = 4 / 1, Rf = 0.5). The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to afford 1-bromo- 3 -(3 -methoxypropoxy )-5 -nitrobenzene (26.4 g, 99%) as an orange oil crude. The crude was used for next step directly without purification.

[0198] Step 2: 3-Bromo-5-(3-methoxypropoxy)aniline. A mixture of l-bromo-3-(3- methoxypropoxy)-5-nitrobenzene (13 g, 45 mmol, 1 equiv.) and H2O (24 mL) in EtOH (120 mL) were added NH4CI (11.98 g, 224 mmol, 5 equiv.) and iron (12.51 g, 224 mmol, 5 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3: 1) to afford 3-bromo-5-(3-methoxypropoxy)aniline (7.1 g, 61%) as a yellow oil.C10H14BrNO2: MW 260. LC-MS (ESI, m / z): [M + H]+ = 260, 262. 1H NMR (300 MHz, Chloroform-d) 5 6.49 (t, J = 1.9 Hz, 1H), 6.46 (t, J = 1.8 Hz, 1H), 6.16 (t, J = 2.1 Hz, 1H), 3.98 (t, J = 6.3 Hz, 2H), 3.52 (t, J = 6.2 Hz, 2H), 3.35 (s, 3H), 2.06 - 1.94 (m, 2H).

[0199] Step 3: l-Benzoyl-3-[3-bromo-5-(3-methoxypropoxy)phenyl]thiourea. Into a 250 mL round-bottom flask were added 3-bromo-5-(3-methoxypropoxy)aniline (9 g, 34.598 mmol, 1WSGR Docket No. 20012-705.601 equiv.) , benzoyl isothiocyanate (5.65 g, 34.6 mmol, 1 equiv.) and acetone (50 mL) at room temperature. The resulting mixture was stirred for 3 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1) to afford l-benzoyl-3-[3-bromo-5-(3-methoxypropoxy)phenyl]thiourea (11 g, 75%) as a yellow solid. C18H19BrN2O3S: MW 423. LC-MS (ESI, m / z): [M + H]+ = 423, 425. 1H NMR (400 MHz, Chloroform-d) 5 12.64 (s, 1H), 9.04 (s, 1H), 7.91 - 7.89 (m, 1H), 7.88 - 7.87 (m, 1H), 7.70 - 7.64 (m, 1H), 7.59 - 7.53 (m, 2H), 7.47 (t, J = 1.8 Hz, 1H), 7.42 (t, J = 2.1 Hz, 1H), 6.98 (t, J = 2.0 Hz, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.55 (t, J = 6.1 Hz, 2H), 3.36 (s, 3H), 2.11 - 2.01 (m, 2H).

[0200] Step 4: 3-Bromo-5-(3-methoxypropoxy)phenylthiourea. Into a 500 mL 3-necked roundbottom flask were added l-benzoyl-3-[3-bromo-5-(3-methoxypropoxy)phenyl]thiourea (11 g, 25 mmol, 1 equiv.) and NaOH aqueous solution (100 mL, 10%) at room temperature. The resulting mixture was stirred for 2 h at 80 °C. Desired product could be detected by LCMS. The mixture was allowed to cool down to 0 °C. The mixture was acidified to pH 7 with cone. HC1. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford 3-bromo-5-(3- methoxypropoxy)phenylthiourea (7.26 g, 88%) as a yellow solid. Cl lH15BrN2O2S: MW 319. LC-MS (ESI, m / z): [M + H]+ = 319, 321. 1H NMR (300 MHz, Chloroform-d) 5 8.21 (s, 1H), 7.01 (t, J = 1.7 Hz, 1H), 6.98 (t, J = 1.7 Hz, 1H), 6.72 (t, J = 2.1 Hz, 1H), 6.28 (s, 2H), 4.04 (t, J = 6.3 Hz, 2H), 3.53 (t, J = 6.0 Hz, 2H), 3.35 (s, 3H), 2.10 - 1.98 (m, 2H).

[0201] Step 5: 7-Bromo-5-(3-methoxypropoxy)-l,3-benzothiazol-2-amine. Into a 250 mL round-bottom flask were added 3-bromo-5-(3-methoxypropoxy)phenylthiourea (7.0 g, 22 mmol, 1 equiv.) and ACN (20 mL) at 0 °C. To the above mixture was added bromine (3.50 g, 21.9 mmol, 1 equiv.) dropwise over 5 min at 0 °C. The resulting mixture was stirred for an additional 1 h at 0 °C. The desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with water (3 x 10 mL). The solid was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford 7-bromo-5-(3-methoxypropoxy)- l,3-benzothiazol-2-amine (6.0 g, 86%) as an orange oil. Cl lH13BrN2O2S: MW 317. LC-MS (ESI, m / z): [M + H]+ = 317, 319. 1H NMR (300 MHz, Chloroform-d) 5 9.30 (s, 2H), 7.09 (s, 1H), 7.02 (s, 1H), 4.08 (t, J = 6.2 Hz, 2H), 3.54 (t, J = 5.8 Hz, 2H), 3.36 (s, 3H), 2.14 - 2.00 (m, 2H).

[0202] Step 6: 7-Bromo-2-chloro-5-(3-methoxypropoxy)-l,3-benzothiazole. A mixture of 7- bromo-5-(3-methoxypropoxy)-l,3-benzothiazol-2-amine (3 g, 9.458 mmol, 1 equiv.) in ACN (20 mL) were added tert-butyl nitrite (5.85 g, 56.7 mmol, 6 equiv.) and CuCl (2.81 g, 28.4WSGR Docket No. 20012-705.601 mmol, 3 equiv.) in portions at 0 °C. The resulting mixture was stirred for 4 h at 30 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 : 1) to afford 7-bromo-2-chloro-5-(3-methoxypropoxy)- 1,3 -benzothiazole (1.57 g, 49%) as a yellow oil. Cl 1H1 lBrClNO2S: MW 336. LC-MS (ESI, m / z): [M + H]+ = 336, 338. 1H NMR (400 MHz, Chloroform-d) 5 7.40 (dd, J = 12.7, 2.2 Hz, 1H), 7.25 - 7.19 (m, 1H), 4.11 (t, J = 6.3 Hz, 2H), 3.56 (t, J = 6.1 Hz, 2H), 3.36 (s, 3H), 2.12 - 2.03 (m, 2H).

[0203] Step 7: 7-Bromo-5-(3-methoxypropoxy)-l,3-benzothiazole-2-thiol. A mixture of 7- bromo-2-chloro-5-(3-methoxypropoxy)-l,3-benzothiazole (200 mg, 0.594 mmol, 1 equiv.) in MeOH (3 mL) was added NaSH (66.6 mg, 1.19 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred for 2 h at 70 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 7-bromo-5-(3- methoxypropoxy)-l,3-benzothiazole-2-thiol (142 mg, 71.51%) as a light yellow solid.Cl lH12BrNO2S2: MW 334. LC-MS (ESI, m / z): [M + H]+ = 334. 1H NMR (400 MHz, Chloroform-d) 5 9.97 (s, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 4.06 (t, J = 6.3 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.36 (s, 3H), 2.11 - 2.01 (m, 2H).

[0204] Step 8: {[7-Bromo-5-(3-methoxypropoxy)-l,3-benzothiazol-2-yl]sulfanyl}amine. Into a 40 mL vial were added NaClO (0.647 mL, 0.503 mmol, 1.2 equiv., 5%) and aqueous ammonia (1 mL, 25%) at -10 °C. The resulting mixture was stirred for 15 min at -10 °C. To the above mixture were added KOH (0.293 mL, 1.0 M in water) and 7-bromo-5-(3-methoxypropoxy)-l,3- benzothiazole-2-thiol (140 mg, 0.419 mmol, 1 equiv.) at -10 °C. The resulting mixture was stirred for additional 1 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. Cl lH13BrN2O2S2: MW 349. LC-MS (ESI, m / z): [M + H]+ = 349, 351.

[0205] Step 9: 7-Bromo-5-(3-methoxypropoxy)-l,3-benzothiazole-2-sulfonamide. A solution of {[7-bromo-5-(3-methoxypropoxy)-l,3-benzothiazol-2-yl]sulfanyl}amine (142 mg, 0.407 mmol, 1 equiv.) in THF (3 mL) was added mCPBA (281 mg, 1.63 mmol, 4 equiv.) at room temperature. The resulting mixture was stirred for 2 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was purified by reverse flash chromatography with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 10% B in 3 min; 10% B to 25% B in 5 min; 25% B to 80% B in 25 min; 80% B to 95% B in 5 min;WSGR Docket No. 20012-705.601Detector, 254 nm) to give 7-bromo-5-(3-methoxypropoxy)-l,3-benzothiazole-2-sulfonamide (74 mg, 48%) as a white solid. Cl lH13BrN2O4S2: MW 381. LC-MS (ESI, m / z): [M + H]+ = 381, 383. 1H NMR (300 MHz, DMSO-d6) 5 8.45 (s, 2H), 7.74 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.50 (t, J = 6.3 Hz, 2H), 3.26 (s, 3H), 2.07 - 1.91 (m, 2H).Example 8, methyl 2-sulfamoylbenzord]thiazole-4-carboxylate

[0206] Step 1 : Methyl 2-amino-3 -fluorobenzoate. To a stirred mixture of methyl 3-fluoro-2- nitrobenzoate (5.0 g, 25 mmol, 1 equiv.) and iron (7.01 g, 126 mmol, 5 equiv.) in EtOH (30 mL) and H2O (20 mL) was added NH4CI (6.72 g, 126 mmol, 5 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 80 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOH (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0% - 100%) to afford methyl 2-amino-3 -fluorobenzoate (3.8 g, 89%) as a white solid. C8H8FNO2: MW 169. LC-MS (ESI, m / z): [M + H]+ = 170. 1H NMR (300 MHz, Chloroform-d) 5 7.64 (dt, J = 8.2, 1.3 Hz, 1H), 7.10 (ddd, J = 11.3, 7.9, 1.5 Hz, 1H), 6.56 (td, J = 8.1, 5.1 Hz, 1H), 5.66 (s, 2H), 3.88 (s, 3H).

[0207] Step 2: Methyl 2-sulfanylidene-3H-l,3-benzothiazole-4-carboxylate. To a stirred solution of methyl 2-amino-3 -fluorobenzoate (2.8 g, 17 mmol, 1 equiv.) and DBU (6.60 mL, 44.2 mmol, 2.7 equiv.) in toluene (28 mL, 263 mmol) was added CS2 (2.64 mL, 6.21 mmol, 2 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 24 h at 100 °C. The desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0% - 80%) to afford methyl 2-sulfanylidene-3H-l,3-benzothiazole-4-carboxylate (2.4 g, 64%) as a red solid. C9H7NO2S2: MW 225. LC-MS (ESI, m / z): [M + H]+ = 226. 1H NMR (400 MHz, Chloroform-d) 5 11.46 (s, 1H), 7.97 (dd, J = 7.9, 1.1 Hz, 1H), 7.60 (dd, J = 7.9, 1.1 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 4.01 (s, 3H).

[0208] Step 3: Methyl 2-(aminosulfanyl)-l,3-benzothiazole-4-carboxylate. To a stirred solution ofNH3.H2O (32 mL, 25%) and NaQO (14.4 mL, 0.533 mmol, 14.5%) was added dropwise a solution of methyl 2-sulfanylidene-3H-l,3-benzothiazole-4-carboxylate (2.4 g, 11 mmol, 1WSGR Docket No. 20012-705.601 equiv.) and NaOH (511 mg, 12.8 mmol, 1.2 equiv., dissolved in H2O (6.48 mL)) dropwise at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with H2O (3 x 5 mL). The resulting mixture was concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification. C9H8N2O2S2: MW 240. LC-MS (ESI, m / z): [M + H]+ = 241.

[0209] Step 4: Methyl 2-sulfamoyl-l,3-benzothiazole-4-carboxylate. To a stirred solution of methyl 2-(aminosulfanyl)-l,3-benzothiazole-4-carboxylate (100 mg, 0.416 mmol, 1 equiv.) in DME (1 mL) was added m-CPBA (144 mg, 0.832 mmol, 2 equiv.) in portions at -10 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Cl 8, 80 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 4 min; 5% B to 50% B in 30 min; 50% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford methyl 2-sulfamoyl-l,3-benzothiazole- 4-carboxylate (25.6 mg, 22.25%) as a white solid. C9H8N2O4S2: MW 272. LC-MS (ESI, m / z): [M + H]+ = 273. 1H NMR (400 MHz, DMSO-d6) 5 8.52 (dd, J = 8.1, 1.2 Hz, 1H), 8.44 (s, 2H), 8.09 (dd, J = 7.4, 1.2 Hz, 1H), 7.74 (dd, J = 8.2, 7.5 Hz, 1H), 3.94 (s, 3H).Example 9, 2-sulfamoylbenzo[d1thiazole-4-carboxylic acid

[0210] Step 1 : 2-Sulfamoyl-l,3-benzothiazole-4-carboxylic acid. A mixture of methyl 2- sulfamoyl-l,3-benzothiazole-4-carboxylate (100 mg, 0.367 mmol, 1 equiv.) and LiOH.J O (46.23 mg, 1.101 mmol, 3 equiv.) in H2O (1 mL) and THF (1 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: C18, 80 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 4 min; 5% B to 50% B in 30 min; 50% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 2- sulfamoyl-l,3-benzothiazole-4-carboxylic acid (80 mg, 80.13%) as a white solid.C8H6N2O4S2: MW 258. LC-MS (ESI, m / z): [M + H]+ = 259. 1H NMR (400 MHz, DMSO-d6) 5 8.60 - 8.30 (m, 3H), 8.06 (dd, J = 7.4, 1.2 Hz, 1H), 7.77 - 7.68 (m, 1H).Example 10. tert-butyl ethyl(6-(3-hydroxypropoxy)-2-sulfamoylbenzo[d1thiazol-7- yDcarbamateWSGR Docket No. 20012-705.601

[0211] Step 1 : 2-Bromo-l,3-benzothiazol-6-ol. A mixture of 2-bromo-6-methoxy-l,3- benzothiazole (11 g, 45.062 mmol, 1 equiv.) and BBr3 (90.12 mL, 90.124 mmol, 2 equiv.) in DCM (100 mL) was stirred overnight at 40 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-bromo-l,3-benzothiazol-6-ol (9.50 g, 92%) as a brown solid. C7H4BrNOS: MW 230. LC-MS (ESI, m / z): [M + H]+ = 230, 232. 1H NMR (400 MHz, DMSO-d6) 5 9.98 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.8, 2.5 Hz, 1H).

[0212] Step 2: 2-Bromo-7-nitro-l,3-benzothiazol-6-ol. To a stirred solution of 2-bromo-l,3- benzothiazol-6-ol (9 g, 39.117 mmol, 1 equiv.) in H2SO4 (90 mL) was added KNO3 (3.95 g, 39.1 mmol, 1 equiv.) and H2O (15 mL) in portions at -5 °C. The resulting mixture was stirred for 2 h at -5 °C. The desired product could be detected by LCMS. The resulting mixture was diluted with water (60 mL). The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-bromo-7-nitro-l,3-benzothiazol-6-ol (10.5 g, 98%) as a yellow solid. C7H3BrN2O3S: MW 275. LC-MS (ESI, m / z): [M + H]+ = 275, 277. 1H NMR (400 MHz, Methanol-d4) 5 8.18 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H).

[0213] Step 3: 2-Bromo-7-nitro-6-(prop-2-en-l-yloxy)-l,3-benzothiazole. To a stirred mixture of 2-bromo-7-nitro-l,3-benzothiazol-6-ol (10 g, 36.4 mmol, 1 equiv.) and allyl bromide (5.28 g, 43.6 mmol, 1.2 equiv.) in acetone (100 mL) were added Nal (6.54 g, 43.6 mmol, 1.2 equiv.) and K2CO3 (7.54 g, 54.5 mmol, 1.5 equiv.) in portions at room temperature. The resulting mixture was stirred for 24 h at 60 °C. The desired product could be detected by LCMS. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 40%) to afford 2-bromo-7-nitro-6-(prop-2-en-l-yloxy)- 1,3 -benzothiazole (8.00 g, 70%) as a yellow solid. C10H7BrN2O3S: MW 315. LC-MS (ESI, m / z): [M + H]+ = 315, 317. 1H NMR (400 MHz, Chloroform-d) 5 8.15 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 9.1 Hz, 1H), 6.17 - 6.03 (m, 1H), 5.60 (dq, J = 17.3, 1.6 Hz, 1H), 5.41 (dq, J = 10.6, 1.4 Hz, 1H), 4.84 (dt, J = 5.0, 1.7 Hz, 2H).WSGR Docket No. 20012-705.601

[0214] Step 4: 2-Bromo-6-(prop-2-en-l-yloxy)-l,3-benzothiazol-7-amine. To a stirred mixture of 2-bromo-7-nitro-6-(prop-2-en-l-yloxy)-l,3-benzothiazole (8.00 g, 25.4 mmol, 1 equiv.) and iron (7.09 g, 127 mmol, 5 equiv.) in EtOH (100 mL) was added AcOH (14.5 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at 80 °C. The desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 30%) to afford 2-bromo-6-(prop-2-en- l-yloxy)-l,3-benzothiazol-7-amine (6.8 g, 94%) as a yellow solid. C10H9BrN2OS: MW 285. LC-MS (ESI, m / z): [M + H]+ = 285, 287. 1H NMR (400 MHz, Chloroform-d) 5 7.40 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 6.14 - 6.02 (m, 1H), 5.42 (dq, J = 17.3, 1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.4 Hz, 1H), 4.64 (dt, J = 5.4, 1.5 Hz, 2H), 3.94 (s, 2H).

[0215] Step 5: tert-butyl N-[2-bromo-6-(prop-2-en-l-yloxy)-l,3-benzothiazol-7-yl]carbamate. A mixture of 2-bromo-6-(prop-2-en-l-yloxy)-l,3-benzothiazol-7-amine (6.4 g, 22.4 mmol, 1 equiv.) and di-tert-butyl dicarbonate(39.19 g, 180 mmol, 8 equiv.) in methanol (100 mL) was stirred overnight at 60 °C. The desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford tert-butyl N-[2-bromo-6-(prop-2-en-l-yloxy)-l,3- benzothiazol-7-yl]carbamate (6.1 g, 71%) as a white solid. C15H17BrN2O3S: MW 385. LC-MS (ESI, m / z): [M + H]+ = 385, 387. 1H NMR (300 MHz, Chloroform-d) 5 7.68 (d, J = 8.9 Hz, 1H), 7.09 (s, 1H), 7.02 (s, 1H), 6.16 - 5.98 (m, 1H), 5.42 (dq, J = 17.3, 1.6 Hz, 1H), 5.34 (dq, J = 10.6, 1.3 Hz, 1H), 4.67 (dt, J = 5.4, 1.5 Hz, 2H), 1.55 (s, 9H).

[0216] Step 6: tert-butyl N-[2-bromo-6-(prop-2-en-l-yloxy)-l,3-benzothiazol-7-yl]-N- ethylcarbamate. To a stirred solution of tert-butyl N-[2-bromo-6-(prop-2-en-l-yloxy)-l,3- benzothiazol-7-yl]carbamate (6.00 g, 15.6 mmol, 1 equiv.) in DMF (60 mL) was added NaH (0.75 g, 19 mmol, 1.2 equiv., 60%) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature under nitrogen atmosphere. To the above mixture was added ethyl iodide (2.91 g, 18.7 mmol, 1.2 equiv.) dropwise at room temperature. The resulting mixture was stirred for an additional 1 h at room temperature. The desired product could be detected by LCMS. The reaction was quenched with Water / Ice at 0 °C. The resulting mixture was diluted with water (400 mL). The resulting mixture was extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reducedWSGR Docket No. 20012-705.601 pressure. This resulted in tert-butyl N-[2-bromo-6-(prop-2-en-l-yloxy)-l,3-benzothiazol-7-yl]- N-ethylcarbamate (5.00 g, 78%) as a brown solid. C17H21BrN2O3S: MW 413. LC-MS (ESI, m / z): [M + H]+ = 413, 415. 1H NMR (400 MHz, Chloroform-d) 5 7.82 (d, J = 8.9 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 6.09 - 5.96 (m, 1H), 5.42 (dq, J = 17.2, 1.6 Hz, 1H), 5.29 (dd, J = 10.7, 1.7 Hz, 1H), 4.68 - 4.60 (m, 2H), 3.85 - 3.65 (m, 1H), 3.63 - 3.45 (m, 1H), 1.29 (s, 9H), 1.08 (t, J = 7.3 Hz, 3H).

[0217] Step 7: tert-butyl N-[2-bromo-6-(3-hydroxypropoxy)-l,3-benzothiazol-7-yl]-N- ethylcarbamate. A mixture of tert-butyl N-[2-bromo-6-(prop-2-en-l-yloxy)-l,3-benzothiazol-7- yl]-N-ethylcarbamate (4.80 g, 11.6 mmol, 1 equiv.) and 9-borabicyclo[3.3.1]nonane (69.7 mL, 34.8 mmol, 3 equiv.) in THF was stirred overnight at 70 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the above mixture were added EtOH (35 mL), NaOH (35 mL, 4 M) and H2O2 (35 mL, 30%) in portions at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature. The desired product could be detected by LCMS. The reaction was quenched with sat. sodium hyposulfite (aq.) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30% - 50%) to afford tert-butyl N-[2-bromo-6-(3- hydroxypropoxy)-l,3-benzothiazol-7-yl]-N-ethylcarbamate (2.8 g, 56%) as a yellow solid. C17H23BrN2O4S: MW 431. LC-MS (ESI, m / z): [M + H]+ = 431, 433.

[0218] Step 8 : tert-butyl N-(2-bromo-6-{3-[(tert-butyldimethylsilyl)oxy]propoxy}-l,3- benzothiazol-7-yl)-N-ethylcarbamate. To a stirred mixture of tert-butyl N-[2-bromo-6-(3- hydroxypropoxy)-l,3-benzothiazol-7-yl]-N-ethylcarbamate (500 mg, 1.16 mmol, 1 equiv.) and imidazole (158 mg, 2.32 mmol, 2 equiv.) in DMF (5 mL) was added t-butyldimethylchlorosilane (300 mg, 1.39 mmol, 1.2 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl N-(2-bromo-6-{3- [(tert-butyldimethylsilyl)oxy]propoxy}-l,3-benzothiazol-7-yl)-N-ethylcarbamate (570 mg, 90%) as a yellow solid. C23H37BrN2O4SSi: MW 546. LC-MS (ESI, m / z): [M + H]+ = 545, 547. 1H NMR (400 MHz, Chloroform-d) 5 7.82 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 8.9 Hz, 1H), 4.16 (t, J = 6.1 Hz, 2H), 3.86 - 3.74 (m, 3H), 3.56 - 3.42 (m, 1H), 2.04 - 1.95 (m, 2H), 1.54 (s, 3H), 1.29 (s, 6H), 1.14 - 1.04 (m, 3H), 0.89 (s, 9H), 0.05 (s, 6H).WSGR Docket No. 20012-705.601

[0219] Step 9 : tert-butyl N-(6-{3-[(tert-butyldimethylsilyl)oxy]propoxy}-2-sulfamoyl-l,3- benzothiazol-7-yl)-N-ethylcarbamate. To a stirred solution of tert-butyl N-(2-bromo-6-{3-[(tert- butyldimethylsilyl)oxy]propoxy}-l,3-benzothiazol-7-yl)-N-ethylcarbamate (460 mg, 0.843 mmol, 1 equiv.) in THF (5 mL) was added chloro(isopropyl)magnesium (1.26 mL, 2.53 mmol, 3 equiv.) dropwise at -40 °C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. To the above mixture was added tert- butoxy(sulfmylidene)amine (342 mg, 2.53 mmol, 3 equiv.) dropwise at -78°C. The resulting mixture was stirred for an additional 12 h at room temperature. The desired product could be detected by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford tertbutyl N-(6-{3-[(tert-butyldimethylsilyl)oxy]propoxy}-2-sulfamoyl-l,3-benzothiazol-7-yl)-N- ethylcarbamate (210 mg, 46%) as a yellow solid. C23H39N3O6S2Si: MW 546. LC-MS (ESI, m / z): [M + H]+ = 546.

[0220] Step 10: tert-butyl N-ethyl-N-[6-(3-hydroxypropoxy)-2-sulfamoyl-l,3-benzothiazol-7- yl]carbamate. To a stirred solution of tert-butyl N-(6-{3-[(tert-butyldimethylsilyl)oxy]propoxy}- 2-sulfamoyl-l,3-benzothiazol-7-yl)-N-ethylcarbamate (200 mg, 0.366 mmol, 1 equiv.) in THF (2 mL) was added TBAF (0.73 mL, 0.73 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Cl 8, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford tert-butyl N-ethyl-N-[6-(3- hydroxypropoxy)-2-sulfamoyl-l,3-benzothiazol-7-yl]carbamate (100 mg, 63%) as a white solid. C17H25N3O6S2: MW 431. LC-MS (ESI, m / z): [M + H]+ = 432. 1H NMR (400 MHz, DMSO- d6) 5 8.32 (s, 2H), 8.09 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 9.1 Hz, 1H), 4.57 (q, J = 5.1 Hz, 1H), 4.23 (q, J = 6.5 Hz, 2H), 3.76 - 3.63 (m, 1H), 3.57 (q, J = 5.9 Hz, 2H), 3.51 - 3.39 (m, 1H), 1.94 - 1.83 (m, 2H), 1.49 (s, 3H), 1.22 (s, 6H), 1.06 (t, J = 7.2 Hz, 1H), 1.00 (t, J = 7.1 Hz, 2H).Example 11. tert-butyl (2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)(2- sulfamoylbenzo[d1thiazol-7-yl)carbamateWSGR Docket No. 20012-705.601

[0221] Step 1 : Methyl 2-bromo-l,3-benzothiazole-7-carboxylate. A mixture of cupric bromide (6.73 g, 30.1 mmol, 1.7 equiv.) and tert-butyl nitrite (3.29 g, 31.9 mmol, 1.8 equiv.) in dry ACN (30 mL) was stirred for 20 min at room temperature under nitrogen atmosphere. To the above mixture was added methyl 2-amino-l,3-benzothiazole-7-carboxylate (3.8 g, 18 mmol, 1 equiv.) in portions over 5 min at room temperature. The resulting mixture was stirred for additional 6 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved with EtOAc (250 mL) and added with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with 0.5 N HC1 (2 x 50 mL), saturated sodium bicarbonate (200 mL), brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7: 1) to afford methyl 2-bromo-l,3-benzothiazole-7- carboxylate (3.8 g, 77%) as a white solid. C9H6BrNO2S: MW 272. LC-MS (ESI, m / z): [M + H]+ = 272, 274. 1H NMR (400 MHz, Chloroform-d) 5 8.18 (dd, J = 8.0, 1.2 Hz, 1H), 8.12 (dd, J = 7.6, 1.2 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 4.03 (s, 3H).

[0222] Step 2: 2-Bromo-l,3-benzothiazole-7-carboxylic acid. A solution of methyl 2-bromo- l,3-benzothiazole-7-carboxylate (4.7 g, 17 mmol, 1 equiv.) in THF (100 mL) was added with LiOH H2O (2.17 g, 51.8 mmol, 3 equiv.) in H2O (30 mL) at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The reaction was monitored by LCMS. The mixture was diluted with EtOAc (200 mL), acidified to pH 2-3 with 1 N HC1. The organic layer was collected, washed with brine, and dried over Na2SO4. The organic layer was concentrated under reduced pressure to afford 2-bromo-l,3-benzothiazole-7-carboxylic acid (4.3 g, 96%) as white solid. C8H4BrNO2S: MW 258. LC-MS (ESI, m / z): [M - H]- = 256, 258. 1H NMR (400 MHz, DMSO-d6) 5 8.26 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H).

[0223] Step 3: Tert-butyl N-(2-bromo-l,3-benzothiazol-7-yl)carbamate. To a suspension of 2- bromo-l,3-benzothiazole-7-carboxylic acid (2.0 g, 7.75 mmol, 1 equiv.) in dry toluene (60 mL) were added TEA (2.35 g, 23.2 mmol, 3 equiv.), DPPA (2.56 g, 9.30 mmol, 1.2 equiv.) and tertbutanol (0.039 mL, 0.40 mmol) at room temperature. The mixture was heated at 80 °C overnight. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford tert-butyl N-(2-bromo-l,3-benzothiazol-7-yl)carbamate (900 mg, 35%) as a white solid.WSGR Docket No. 20012-705.601C12H13BrN2O2S: MW 329. LC-MS (ESI, m / z): [M + H]+ = 329, 331. 1H NMR (400 MHz, Chloroform-d) 5 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 - 7.39 (m, 2H), 6.50 (s, 1H), 1.55 (s, 9H).

[0224] Step 4: Tert-butyl N-(2-{2-[(2-bromo-l,3-benzothiazol-7-yl)(tert- butoxycarbonyl)amino]ethoxy (ethyl) carbamate. A mixture of NaH (79.0 mg, 1.98 mmol, 1.3 equiv., 60%) and tert-butyl N-(2-bromo-l,3-benzothiazol-7-yl)carbamate (500 mg, 1.52 mmol, 1 equiv.) in dry DMF (3 mL) was stirred for 30 mins at 0 °C under nitrogen atmosphere. To the above mixture was added tert-butyl N-[2-(2-bromoethoxy)ethyl] carbamate (529 mg, 1.98 mmol, 1.3 equiv.) at 0 °C. The resulting mixture was stirred for an additional 16 h at room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4CI (aq., 50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3 : 1) to afford tert-butyl N-(2-{2-[(2-bromo-l,3-benzothiazol-7-yl)(tert- butoxycarbonyl)amino]ethoxy(ethyl)carbamate (400 mg, 51%) as a white semi-solid.C21H30BrN3O5S: MW 516. LC-MS (ESI, m / z): [M + Na]+ = 538 and 540. 1H NMR (400 MHz, Chloroform-d) 5 7.88 (dd, J = 8.1, 0.9 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 6.8 Hz, 1H), 4.78 (s, 1H), 3.86 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.42 (t, J = 5.2 Hz, 2H), 3.22 (q, J = 5.3 Hz, 2H), 1.58 - 1.28 (m, 18H).

[0225] Step 5: Tert-butyl N-(2-{2-[(tert-butoxycarbonyl)(2-sulfamoyl-l,3-benzothiazol-7- yl)amino] ethoxy (ethyl) carbamate. In a 50-mL round bottom flask was added a solution of tertbutyl N-(2-{2-[(2-bromo-l,3-benzothiazol-7-yl)(tert- butoxycarbonyl)amino]ethoxy(ethyl)carbamate (350 mg, 0.678 mmol, 1 equiv.) in 4 mL dry THF (2 mL) and i-PrMgCl (1.02 mL, 2.03 mmol, 3 equiv.) at -40 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h. Then a solution of tert- butoxy(sulfinylidene)amine (275 mg, 2.03 mmol, 3 equiv.) in 2 mL dry THF was added to the above mixture. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (10 mL), and then the mixture was extracted with EtOAc (3*100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified first by reversed-phase flash chromatography with the following conditions: (column, C18, 40 g ; mobile phase, MeCN in water (10 mmol / L NH4HCO3), Flow rate 70 mL / min, Gradient 5% to 5% in 3 min; 5% to 55% in 25 min; 55% to 55% in 4 min; 55% to 95% in 10 min; detector, UV 254 nm) to afford crude. The crude was further purified by Prep-HPLC with the following conditions: (Column: X Bridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3 +WSGR Docket No. 20012-705.6010.1% NH3 H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B to 44% B in 10 min; Wave Length: 254 / 220 nm; RT1 : 12.67 min) to afford tert-butyl N-(2-{2-[(tert- butoxycarbonyl)(2-sulfamoyl-l,3-benzothiazol-7-yl)amino]ethoxy}ethyl)carbamate (14 mg, 4%) as white solid. C21H32N4O7S2: MW 517. LC-MS (ESI, m / z): [M - H]- = 515. 1H NMR (400 MHz, DMSO-d6) 5 8.38 (s, 2H), 8.09 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 6.67 (s, 1H), 3.82 (s, 2H), 3.44 (t, J = 5.6 Hz, 2H), 3.27 (t, J = 6.0 Hz, 2H), 2.95 (q, J = 5.6 Hz, 2H), 1.35 (br, s, 18H).Example 12, benzyl 4-(2-((tert-butoxycarbonyl)(2-sulfamoylbenzo[d]thiazol-7- yl)amino)ethyl)piperidine- 1 -carboxylate

[0226] Step 1 : Benzyl 4-(2-hydroxyethyl)piperidine-l -carboxylate. A solution of 4- piperidineethanol (2.0 g, 15 mmol, 1 equiv.) and NEt3 (4.70 g, 46.4 mmol, 3 equiv.) in dry DCM (50 mL) was added with benzyl chloroformate (3.17 g, 18.6 mmol, 1.2 equiv.) dropwise for 5 min at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (20: 1) to afford benzyl 4-(2-hydroxyethyl)piperidine-l -carboxylate (3.6 g, 88%) as a white oil.C15H21NO3: MW 263. LC-MS (ESI, m / z): [M + H]+ = 264. 1H NMR (400 MHz, Chloroform- d) 5 7.39 - 7.28 (m, 5H), 5.12 (s, 2H), 4.16 (d, J = 13.3 Hz, 2H), 3.70 (t, J = 6.5 Hz, 2H), 2.84 - 2.71 (m, 2H), 1.75 - 1.66 (m, 1H), 1.65 - 1.57 (m, 1H), 1.56 - 1.47 (m, 3H), 1.23 - 1.08 (m, 2H).

[0227] Step 2: Benzyl 4-(2-bromoethyl)piperidine-l -carboxylate. A solution of benzyl 4-(2- hydroxyethyl)piperidine-l -carboxylate (1.0 g, 3.8 mmol, 1 equiv.) and CBr4 (1.89 g, 5.70 mmol, 1.5 equiv.) in dry DCM (15 mL) was added PPh3 (1.49 g, 5.70 mmol, 1.5 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (Rf = 0.4, PE : EA = 3 : 1). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / MTBE (2: 1) to afford benzyl 4- (2-bromoethyl)piperidine-l -carboxylate (1.1 g, 89%) as a colorless semi-solid. C15H20BrNO2: MW 326. LC-MS (ESI, m / z): [M + H]+ = 326, 328. 1H NMR (400 MHz, Chloroform-d) 5 7.40 - 7.28 (m, 5H), 5.12 (s, 2H), 4.19 (d, J = 13.5 Hz, 2H), 3.44 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 12.7 Hz, 2H), 1.81 (q, J = 6.7 Hz, 2H), 1.76 - 1.63 (m, 3H), 1.20 - 1.07 (m, 2H).WSGR Docket No. 20012-705.601

[0228] Step 3: Benzyl 4-{2-[(2-bromo-l,3-benzothiazol-7-yl)(tert- butoxycarbonyl)amino]ethyl (piperidine- 1 -carboxylate. To a solution of tert-butyl-N-(2-bromo-1.3-benzothiazol-7-yl)carbamate (500 mg, 1.52 mmol, 1 equiv.) in dry DMF (5 mL) was added NaH (79.0 mg, 1.98 mmol, 1.3 equiv., 60%) at 0 °C. The mixture was stirred for 30 mins at 0 °C. Tert-butyl-N-(2-bromo-l,3-benzothiazol-7-yl)carbamate (500 mg, 1.52 mmol, 1 equiv.) was added to the above mixture. The mixture was allowed to warm to room temperature and stirred for an additional 3 h at 80 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction mixture was quenched by water (50 mL) and extracted with EtOAc (3*80 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3: 1) to afford benzyl 4-{2-[(2-bromo-l,3-benzothiazol-7-yl)(tert-butoxycarbonyl)amino]ethyl( piperidine- 1 -carboxylate (680 mg, 78%) as a colorless semi-solid. C27H32BrN3O4S: MW 575. LC-MS (ESI, m / z): [M -56 + H]+ = 518, 520. 1H NMR (400 MHz, Chloroform-d) 5 7.89 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.39 - 7.29 (m, 5H), 7.22 (d, J = 7.6 Hz, 1H), 5.10 (s, 2H), 4.24 - 4.03 (m, 2H), 3.72 (t, J = 6.8 Hz, 2H), 2.72 (s, 2H), 1.65 (br, s, 2H), 1.54 - 1.22 (m, 12H), 1.16 - 1.03 (m, 2H).

[0229] Step 4: Benzyl 4-{2-[(tert-butoxycarbonyl)(2-sulfanyl-l,3-benzothiazol-7- yl)amino] ethyl (piperidine- 1 -carboxylate. A mixture of benzyl 4-{2-[(2-bromo-l,3-benzothiazol- 7-yl)(tert-butoxycarbonyl)amino]ethyl (piperidine- 1 -carboxylate (350 mg, 0.609 mmol, 1 equiv.) and sodium hydrosulfide (171 mg, 3.05 mmol, 5 equiv.) in EtOH (7 mL) was stirred for 5 h at 80 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel, 90 g; mobile phase, MeCN in Water (10 mmol / L NH4HCO3); Flow rate 55 mL / min; Gradient: 5% B to 50% B in 25 min, 50% B to 50% B in 10 min; detector, UV 254 / 220 nm) to afford benzyl 4-{2-[(tert-butoxycarbonyl)(2-sulfanyl-1.3-benzothiazol-7-yl)amino] ethyl (piperidine- 1 -carboxylate (200 mg, 62%) as a white solid. C27H33N3O4S2: MW 528. LC-MS (ESI, m / z): [M + Na]+ = 550. 1H NMR (400 MHz, DMSO- d6) 5 13.84 (s, 1H), 7.45 - 7.27 (m, 6H), 7.25 - 7.16 (m, 2H), 5.04 (s, 2H), 3.96 (d, J = 13.0 Hz, 2H), 3.63 (t, J = 7.3 Hz, 2H), 2.72 (s, 2H), 1.59 (d, J = 12.9 Hz, 2H), 1.48 - 1.24 (m, 12H), 1.04 - 0.91 (m, 2H).

[0230] Step 5: Benzyl 4-(2-{[2-(aminosulfanyl)-l,3-benzothiazol-7-yl](tert- butoxycarbonyl)amino(ethyl)piperidine-l-carboxylate. To a stirred solution of NaClO (2.0 mL, 2.4 mmol, 12 equiv., 8% aq.) was dropped slowly NH3.H2O (2 mL, 12.8 mmol, 68 equiv., 25%) at 00C. The resulting mixture was stirred for 0.5 h at 00C. Then benzy-4-{2-[(tert-WSGR Docket No. 20012-705.601 butoxy carbonyl)(2-sulfanyl-l,3-benzothiazol-7-yl)amino]ethyl(piperidine-l -carboxylate (100 mg, 0.190 mmol, 1 equiv., dissolved in 1 mL of 2M NaOH aq.) was added to the above mixture. The resulting mixture was stirred for additional 1 h at 0 °C. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with water (3x10 mL). The resulting mixture was concentrated under reduced pressure to afford benzyl 4-(2-{[2- (aminosulfanyl)-l,3-benzothiazol-7-yl](tert-butoxycarbonyl)amino(ethyl)piperidine-l- carboxylate (60 mg, 58%) as white solid. C27H34N4O4S2: MW 543. LC-MS (ESI, m / z): [M + H]+ = 543.

[0231] Step 6: Benzyl 4-{2-[(tert-butoxycarbonyl)(2-sulfamoyl-l,3-benzothiazol-7- yl)amino] ethyl (piperidine- 1 -carboxylate. A solution of benzyl 4-(2-{[2-(aminosulfanyl)-l,3- benzothiazol-7-yl](tert-butoxycarbonyl)amino(ethyl) piperidine- 1 -carboxylate (50 mg, 0.092 mmol, 1 equiv.) in DCM (3 mL) was added with mCPBA (79 mg, 0.46 mmol, 5 equiv.) in portions at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel, 48 g; mobile phase, MeCN in Water (10 mmol / L NH4HCO3); Flow rate 50 mL / min; Gradient: 5% to 65% in 25 min, 65% to 65% in 3 min; detector, UV 254 / 220 nm. This resulted in benzyl 4-{2-[(tert- butoxycarbonyl)(2-sulfamoyl-l,3-benzothiazol-7-yl)amino]ethyl(piperidine-l-carboxylate (35 mg, 64%) as a white solid. C27H34N4O6S2: MW 575. LC-MS (ESI, m / z): [M + H]+ = 575. 1H NMR (400 MHz, DMSO-d6) 5 8.41 (s, 2H), 8.11 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.42 - 7.26 (m, 5H), 5.04 (s, 2H), 3.95 (d, J = 13.1 Hz, 2H), 3.74 (t, J = 7.0 Hz, 2H), 2.71 (br, s, 2H), 1.58 (d, J = 12.8 Hz, 2H), 1.53 - 1.11 (m, 12H), 1.04 - 0.91 (m, 2H).Example 13, 7-((2-(piperidin-4-yl)ethyl)amino)benzo[d1thiazole-2-sulfonamide

[0232] Step 1 : 7-{[2-(Piperidin-4-yl)ethyl]amino}-l,3-benzothiazole-2-sulfonamide. A solution of benzyl 4-{2-[(tert-butoxycarbonyl)(2-sulfamoyl-l,3-benzothiazol-7- yl)amino]ethyl (piperidine- 1 -carboxylate (120 mg, 0.209 mmol, 1 equiv.) in ACN (3 mL) was added with TMSI (0.0746 mL, 0.522 mmol, 2.5 equiv.) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. To the above mixture was added additional TMSI (0.0746 mL, 0.522 mmol, 2.5 equiv.) dropwise at room temperature. The resulting mixture was stirred for an additional 2 h at room temperature. TheWSGR Docket No. 20012-705.601 resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel, 80 g; mobile phase, MeCN in Water (10 mmol / L NH4HCO3); Flow rate: 55 mL / min; Gradient, 5% to 32% in 14 min, 32% to 32 % 10 min; detector, UV 254 / 220 nm) to afford 7-{[2-(piperidin-4- yl)ethyl]amino}-l,3-benzothiazole-2-sulfonamide (35 mg, 47%) as a light yellow solid. C14H20N4O2S2: MW 340. LC-MS (ESI, m / z): [M + H]+ = 341. 1H NMR (400 MHz, DMSO- d6) 5 7.44 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.10 (t, J = 5.4 Hz, 1H), 3.24 (q, J = 6.5 Hz, 2H), 3.01 - 2.92 (m, 2H), 2.54 - 2.51 (m, 2H), 2.49 - 2.41 (m, 1H), 1.72 - 1.63 (m, 2H), 1.60 - 1.43 (m, 3H), 1.15 - 1.02 (m, 2H).Example 14, benzyl 4-(3-((tert-butoxycarbonyl)(2-sulfamoylbenzo[d]thiazol-7- yl)amino)propyl)piperidine-l -carboxylate

[0233] Step 1 : Benzyl 4-(3-hydroxypropyl)piperidine-l-carboxylate. A solution of 3-(piperidin- 4-yl)propan-l-ol (2.0 g, 14 mmol, 1 equiv.) and NEt3 (4.24 g, 41.9 mmol, 3 equiv.) in dry DCM (40 mL) was added with benzyl chloroformate (2.86 g, 16.8 mmol, 1.2 equiv.) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (20: 1) to afford benzyl 4-(3-hydroxypropyl) piperidine- 1 -carboxylate (1.6 g, 41%) as a colorless oil.C16H23NO3: MW 277. LC-MS (ESI, m / z): [M + H]+ = 278. 1H NMR (400 MHz, Chloroform- d) 5 7.39 - 7.28 (m, 5H), 5.12 (s, 2H), 4.17 (d, J = 14.8 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.83 - 2.68 (m, 2H), 1.74 - 1.65 (m, 2H), 1.63 - 1.55 (m, 2H), 1.48 - 1.36 (m, 1H), 1.35 - 1.26 (m, 2H), 1.19 - 1.05 (m, 2H).

[0234] Step 2: Benzyl 4-(3-bromopropyl)piperidine-l-carboxylate. A solution of benzyl 4-(3- hydroxypropyl)piperidine-l -carboxylate (1.6 g, 5.8 mmol, 1 equiv.) and CBr4 (2.87 g, 8.65 mmol, 1.5 equiv.) in dry DCM (20 mL) was added PPh3 (2.27 g, 8.65 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (Rf = 0.4, PE : EA = 3 : 1). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / MTBE (2: 1) to afford benzyl 4-(3 -brom opropyl)piperi dine- 1- carboxylate (1.8 g, 92%) as a colorless semi-solid. C16H22BrNO2: MW 340. LC-MS (ESI, m / z): [M + H]+ = 340, 342. 1H NMR (400 MHz, Chloroform-d) 5 7.43 - 7.27 (m, 5H), 5.12 (s,WSGR Docket No. 20012-705.6012H), 4.16 (s, 2H), 3.39 (t, J = 6.8 Hz, 2H), 2.76 (t, J = 12.5 Hz, 2H), 1.93 - 1.82 (m, 2H), 1.67 (d, J = 13.1 Hz, 2H), 1.49 - 1.34 (m, 3H), 1.20 - 1.06 (m, 2H).

[0235] Step 3: Benzyl 4-{3-[(2-bromo-l,3-benzothiazol-7-yl)(tert- butoxycarbonyl)amino]propyl}piperidine-l-carboxylate. To a solution of tert-butyl N-(2-bromo- l,3-benzothiazol-7-yl)carbamate (570 mg, 1.73 mmol, 1 equiv.) in dry DMF (5 mL) was added NaH (83.1 mg, 2.08 mmol, 1.2 equiv., 60%) at 0 °C. The mixture was stirred for 30 min. Benzyl 4-(3-bromopropyl)piperidine-l-carboxylate (707 mg, 2.08 mmol, 1.2 equiv.) was added to the above mixture. The reaction mixture was allowed to warm to 80 °C and stirred for an additional 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3: 1) to afford benzyl 4-{3-[(2-bromo-l,3-benzothiazol-7-yl)(tert-butoxycarbonyl) amino]propyl (piperidine- 1 -carboxylate (820 mg, 80%) as a colorless semi-solid.C28H34BrN3O4S: MW 589. LC-MS (ESI, m / z): [M + Na]+ = 610, 612. 1H NMR (400 MHz, Chloroform-d) 5 7.88 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.37 - 7.28 (m, 5H), 7.22 (d, J = 7.9 Hz, 1H), 5.11 (s, 2H), 4.13 (d, J = 14.3 Hz, 2H), 3.65 (t, J = 7.5 Hz, 2H), 2.71 (t, J = 12.6 Hz, 2H), 1.65 - 1.56 (m, 2H), 1.55 - 1.45 (m, 2H), 1.38 (br, s, 9H), 1.27 - 1.17 (m, 3H), 1.13 - 1.00 (m, 2H).

[0236] Step 4: Benzyl 4-{3-[(tert-butoxycarbonyl)(2-sulfanyl-l,3-benzothiazol-7- yl)amino]propyl(piperidine-l-carboxylate. A solution of benzyl 4-{3-[(2-bromo-l,3- benzothiazol-7-yl)(tert-butoxycarbonyl)amino]propyl(piperidine-l-carboxylate (820 mg, 1.39 mmol, 1 equiv.) in EtOH (12 mL) was added NaSH (391 mg, 6.97 mmol, 5 equiv.) at room temperature. The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL). The resulting mixture was extracted with CHC13 / IPA (3 : 1, 3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford benzyl 4-{3-[(tert- butoxycarbonyl)(2-sulfanyl-l,3-benzothiazol-7-yl)amino]propyl(piperidine-l-carboxylate (700 mg, 93%) as white solid. C28H35N3O4S2: MW 542. LC-MS (ESI, m / z): [M + H]+ = 542. 1H NMR (400 MHz, DMSO-d6) 5 7.40 - 7.27 (m, 5H), 7.23 - 7.12 (m, 2H), 6.90 (d, J = 7.1 Hz, 1H), 5.04 (s, 2H), 3.95 (d, J = 13.2 Hz, 2H), 3.51 (t, J = 7.3 Hz, 2H), 2.72 (br, s, 2H), 1.57 (d, J = 12.7 Hz, 2H), 1.45 - 1.23 (m, 12H), 1.19 - 1.12 (m, 2H), 0.99 - 0.87 (m, 2H).WSGR Docket No. 20012-705.601

[0237] Step 5: Benzyl 4-(3-{[2-(aminosulfanyl)-l,3-benzothiazol-7-yl](tert- butoxycarbonyl)amino(propyl)- piperi dine- 1 -carboxylate. A solution of NaClO (8.0 mL, 9.5 mmol, 7.3 equiv., 8%) and aqueous ammonia (10 mL, 64 mmol, 50 equiv., 25%) were added benzyl 4-{3-[(tert-butoxycarbonyl)(2-sulfanyl-l,3-benzothiazol-7-yl)amino]propyl}piperidine- 1-carboxylate (700 mg, 1.29 mmol, 1 equiv.) and NaOH (7.0 mL, 14 mmol, 11 equiv.) in portions at °C. The resulting mixture was stirred for 1 h at 0 °C. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with water (3 x 50 mL). The solid was dried under reduced pressure to afford benzyl 4-(3-{[2-(aminosulfanyl)-l,3- benzothiazol-7-yl](tert-butoxycarbonyl)amino}propyl)piperidine-l-carboxylate (600 mg, 83%) as white solid. C28H36N4O4S2: MW 557. LC-MS (ESI, m / z): [M + H]+ = 557.

[0238] Step 6: Benzyl 4-{3-[(tert-butoxycarbonyl)(2-sulfamoyl-l,3-benzothiazol-7- yl)amino]propyl (piperidine- 1-carboxylate. A solution of benzyl 4-(3-{[2-(aminosulfanyl)-l,3- benzothiazol-7-yl](tert-butoxycarbonyl)amino(propyl)- piperidine- 1-carboxylate (600 mg, 1.08 mmol, 1 equiv.) in DCM (10 mL) was treated with mCPBA (930 mg, 5.39 mmol, 5 equiv.) in portions at 0 °C. The resulting mixture was stirred for 3 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel, 120 g; mobile phase, MeCN in Water (10 mmol / L NH4HCO3); Flow rate: 60 mL / min; Gradient: 5% to 67% B in 25 min, 67% B to 67% B in 7 min; detector, UV 254 / 220 nm) to afford benzyl 4-{3-[(tert-butoxycarbonyl)(2-sulfamoyl-l,3-benzothiazol-7- yl)amino]propyl(piperidine-l-carboxylate (390 mg, 59%) as a white solid. C28H36N4O6S2: MW 589. LC-MS (ESI, m / z): [M + H]+ = 589. 1H NMR (400 MHz, DMSO-d6) 5 8.42 (s, 2H), 8.11 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.42 - 7.25 (m, 5H), 5.04 (s, 2H), 3.95 (d, J = 13.1 Hz, 2H), 3.69 (t, J = 7.4 Hz, 2H), 2.71 (br, s, 2H), 1.55 (d, J = 12.9 Hz, 2H), 1.50 - 1.22 (m, 12H), 1.21 - 1.13 (m, 2H), 0.99 - 0.86 (m, 2H).Example 15, 7-chloro-6-(3-methoxypropoxy)benzo[d1thiazole-2-sulfonamide

[0239] Step 1 : 2-Bromo-l,3-benzothiazol-6-ol. A mixture of 2-bromo-6-methoxy-l,3- benzothiazole (10 g, 41 mmol, 1 equiv.) and BBr3 (81.9 mL, 81.9 mmol, 2 equiv.) in DCM (100 mL) was stirred for overnight at 40 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (500 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (2 x 400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.WSGR Docket No. 20012-705.601This resulted in 2-bromo-l,3-benzothiazol-6-ol (9.6 g, 98%) as a brown solid. C7H4BrNOS: MW 230. LC-MS (ESI, m / z): [M + H]+ = 230, 232. 1H NMR (300 MHz, DMSO-d6) 5 10.00 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.8, 2.5 Hz, 1H).

[0240] Step 2: 2-Bromo-7-chloro-l,3-benzothiazol-6-ol. To a stirred mixture of 2-bromo-l,3- benzothiazol-6-ol (1 g, 4.346 mmol, 1 equiv.) in DMF (10 mL) was added NCS (0.58 g, 4.3 mmol, 1 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-bromo-7-chloro-l,3-benzothiazol-6-ol (1.2 g, 93%) as a yellow solid. C7H3BrClNOS: MW 265. LC-MS (ESI, m / z): [M + H]+ = 264, 266. 1H NMR (300 MHz, DMSO-d6) 5 10.89 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H).

[0241] Step 3: 2-Bromo-7-chloro-6-(3 -methoxypropoxy)- 1,3 -benzothiazole. To a stirred mixture of 2-bromo-7-chloro-l,3-benzothiazol-6-ol (1.1 g, 4.2 mmol, 1 equiv.) and BGCCL (1.15 g, 8.32 mmol, 2 equiv.) in DMF (10 mL) was added l-bromo-3-methoxypropane (0.95 g, 6.2 mmol, 1.5 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 40%) to afford 2-bromo-7-chloro-6-(3-methoxypropoxy)-l,3-benzothiazole (1.05 g, 75%) as a yellow solid. Cl 1H1 lBrQNO2S: MW 337. LC-MS (ESI, m / z): [M + H]+ = 336, 338. 1H NMR (400 MHz, Chloroform-d) 5 7.81 (d, J = 8.9 Hz, 1H), 7.14 (d, J = 8.9 Hz, 1H), 4.22 (t, J = 6.2 Hz, 2H), 3.61 (t, J = 6.0 Hz, 2H), 3.37 (s, 3H), 2.17 - 2.07 (m, 2H).

[0242] Step 4: 7-Chloro-6-(3-methoxypropoxy)-l,3-benzothiazole-2-sulfonamide. To a stirred mixture of 2-bromo-7-chloro-6-(3-methoxypropoxy)-l,3-benzothiazole (900 mg, 2.67 mmol, 1 equiv.) in THF (18 mL) was added i-PrMgCl (4.01 mL, 8.02 mmol, 3 equiv.) dropwise at -78 °C under argon atmosphere. The resulting mixture was stirred for 1 h at 0 °C under argon atmosphere. To the above mixture was added tert-butoxy(sulfmylidene)amine (1.08 g, 8.02 mmol, 3 equiv.) dropwise at -78 °C. The resulting mixture was stirred for an additional 6 h at room temperature. The desired product could be detected by LCMS. The reaction was quenchedWSGR Docket No. 20012-705.601 with water (5 mL) at room temperature. The resulting mixture was filtered, the filter cake was washed with THF (2 x 2 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Cl 8, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 7-chloro-6-(3-methoxypropoxy)-l,3-benzothiazole-2-sulfonamide (450 mg, 50%) as a white solid. C11H13C1N2O4S2: MW 337. LC-MS (ESI, m / z): [M + H]+ = 337. 1H NMR (400 MHz, DMSO-d6) 5 8.40 (s, 2H), 8.14 (d, J = 9.1, 1H), 7.59 (d, J = 9.1, 1H), 4.29 (t, J = 6.4 Hz, 2H), 3.53 (t, J = 6.3 Hz, 2H), 3.26 (s, 3H), 2.11 - 1.98 (m, 2H).Example 16, Diftert-butyl (6-((3,6,10,14-tetraoxaheptadecan-17-yl)oxy)-2- sulfamoylbenzord1thiazol-7-yl)(ethyl)carbamate-l-yl)ether

[0243] Step 1 : l,31-Diphenyl-2,6,10,13,16,19,22,26,30-nonaoxahentriacontane. To a stirred mixture of tetraethylene glycol (2.0 g, 10 mmol, 1 equiv.) in DMF (20 mL) was added NaH (1.03 g, 25.7 mmol, 2.5 equiv., 60%) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added 3 -[3 -(benzyloxy )propoxy]propyl 4-methylbenzenesulfonate (9.74 g, 25.7 mmol, 2.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred for an additional 2 h at 25 °C. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4CI (300 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 300 mL), the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0% - 50%) to afford l,31-diphenyl-2,6,10,13,16,19,22,26,30- nonaoxahentriacontane (4.2 g, 67%) as a colorless oil. C34H54O9: MW 607. LC-MS (ESI, m / z): [M + H]+ = 607. 1H NMR (300 MHz, CDC13) 5 7.46 - 7.18 (m, 10H), 4.52 (s, 4H), 3.71 - 3.45 (m, 32H), 1.95 - 1.79 (m, 8H).

[0244] Step 2: 4,8,l l,14,17,20,24-Heptaoxaheptacosane-l,27-diol. To a stirred mixture of 1,31- diphenyl-2,6,10,13,16,19,22,26,30-nonaoxahentriacontane (4.2 g, 6.9 mmol, 1 equiv.) and Pd / C (420 mg, 10%) in MeOH (40 mL) at room temperature under hydrogen atmosphere. TheWSGR Docket No. 20012-705.601 resulting mixture was stirred for 12 h at room temperature under H2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford 4,8,11,14,17,20,24- heptaoxaheptacosane-l,27-diol (2.6 g, crude) as a colorless oil. The crude product was used in the next step directly without further purification. C20H42O9: MW 427. LC-MS (ESI, m / z): [M + H]+ = 427. 1H NMR (400 MHz, CDC13) 5 3.76 (t, J = 5.6 Hz, 4H), 3.69 - 3.48 (m, 28H), 2.63 (s, 2H), 1.90 - 1.78 (m, 8H).

[0245] Step 3: l,39-Diphenyl-2,6,10,14,17,20,23,26,30,34,38-undecaoxanonatriacontane. To a stirred mixture of 4,8,11,14, 17,20, 24-heptaoxaheptacosane-l,27-diol (2.0 g, 4.7 mmol, 1 equiv.) in DMF (20 mL) was added NaH (0.47 g, 12 mmol, 2.5 equiv., 60%) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added 3 -(benzyl oxy )propyl 4-methylbenzenesulfonate (3.76 g, 11.7 mmol, 2.5 equiv.) in portion at 0 °C. The resulting mixture was stirred for additional 12 h at room temperature. The reaction was monitored by LCMS. The reaction was quenched with water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL), the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: C18, 330 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 90 mL / min; Gradient: 5% B to 5% B in 5 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 1,39-diphenyl- 2,6,10,14,17,20,23,26,30,34,38-undecaoxanonatriacontane (3.0 g, 89%) as a colorless oil. C40H66O11 : MW 723. LC-MS (ESI, m / z): [M + H]+ = 723. 1H NMR (400 MHz, CDC13) 5 7.37 - 7.24 (m, 10H), 4.50 (s, 4H), 3.69 - 3.41 (m, 40H), 1.93 - 1.76 (m, 12H).

[0246] Step 4: 4,8,12,15,18,21,24,28,32-Nonaoxapentatriacontane-l,35-diol. To a stirred solution of l,39-diphenyl-2,6,10,14,17,20,23,26,30,34,38-undecaoxanonatriacontane (2.9 g, 4.0 mmol, 1 equiv.) in MeOH (20 mL) was added Pd / C (600 mg, 10%) in portions at room temperature under H2 atmosphere. The resulting mixture was stirred for 12 h at room temperature under H2 atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford 4,8,12,15,18,21,24,28,32-nonaoxapentatriacontane-l,35-diol (2 g, crude) as a colorless oil. The crude product was used in the next step directly without further purification. C26H54O11 : MW 543. LC-MS (ESI, m / z): [M + H]+ = 543. 1H NMR (400 MHz, CDC13) 5 3.76 (t, J = 5.6 Hz, 4H), 3.68 - 3.45 (m, 36H), 2.53 (s, 2H), 1.89 - 1.79 (m, 12H).

[0247] Step 5: 2-Bromo-6-({35-[(2-bromo-7-nitro-l,3-benzothiazol-6-yl)oxy]- 4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl}oxy)-7-nitro-l,3-benzothiazole. To aWSGR Docket No. 20012-705.601 stirred mixture of 4,8,12,15,18,21,24,28,32-nonaoxapentatriacontane-l,35-diol (1.9 g, 3.5 mmol, 1 equiv.) and 2-bromo-7-nitro-l,3-benzothiazol-6-ol (2.12 g, 7.70 mmol, 2.2 equiv.), PPh3 (2.75 g, 10.5 mmol, 3 equiv.) in toluene (20 mL) was added DEAD (1.83 g, 10.5 mmol, 3 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 12 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: C18, 330 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 90 mL / min; Gradient: 5% B to 5% B in 5 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 2-bromo-6-({35-[(2-bromo-7- nitro-l,3-benzothiazol-6-yl)oxy]-4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl}oxy)-7- nitro- 1,3 -benzothiazole (1.6 g, 43%) as a yellow solid. C40H56Br2N4O15S2: MW 1057. LCMS (ESI, m / z): [M + H]+ = 1055, 1057. 1H NMR (400 MHz, CDC13) 5 8.16 (d, J = 9.1 Hz, 2H), 7.32 (d, J = 9.1 Hz, 2H), 4.36 (t, J = 6.0 Hz, 4H), 3.73 - 3.41 (m, 36H), 2.56 (s, 1H), 2.21 - 2.13 (m, 4H), 1.87 - 1.77 (m, 8H).

[0248] Step 6: 6-({35-[(7-Amino-2-bromo-l,3-benzothiazol-6-yl)oxy]-4.8.12.15.18.21.24.28.32-nonaoxapentatriacontan-l-yl}oxy)-2-bromo-l,3-benzothiazol-7-amine. A mixture of 2-bromo-6-({35-[(2-bromo-7-nitro-l,3-benzothiazol-6-yl)oxy]-4.8.12.15.18.21.24.28.32-nonaoxapentatriacontan-l-yl}oxy)-7-nitro-l,3-benzothiazole (1.5 g, 1.4 mmol, 1 equiv.), iron (793 mg, 14.2 mmol, 10 equiv.) and NH4CI (456 mg, 8.51 mmol, 6 equiv.) in EtOH (15 mL) and H2O (3 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOH (15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC with the following conditions (Column: Cl 8, 120 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 6-({35-[(7-amino-2- bromo-l,3-benzothiazol-6-yl)oxy]-4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl}oxy)- 2-bromo-l,3-benzothiazol-7-amine (1.3 g, 92%) as a colorless oil. C40H60Br2N4011S2: MW 997. LC-MS (ESI, m / z): [M + H]+ = 995, 997. 1H NMR (300 MHz, CDC13) 5 7.45 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 6.2 Hz, 4H), 3.71 - 3.42 (m, 36H), 2.17 - 2.06 (m, 4H), 1.90 - 1.76 (m, 8H).

[0249] Step 7: Tert-butyl N-(2-bromo-6-{[35-({2-bromo-7-[(tert-butoxycarbonyl)amino]-l,3- benzothiazol-6-yl}oxy)-4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl]oxy}-l,3- benzothiazol-7-yl)carbamate. To a stirred mixture of 6-({35-[(7-amino-2-bromo-l,3- benzothiazol-6-yl)oxy]-4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl}oxy)-2-bromo-WSGR Docket No. 20012-705.6011.3-benzothiazol-7-amine (1.4 g, 1.4 mmol, 1 equiv.) and Boc2O (3.07 g, 14.0 mmol, 10 equiv.) in EtOH (10 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 70 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep- HPLC with the following conditions (Column: Cl 8, 120 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford tert-butyl N-(2- bromo-6-{[35-({2-bromo-7-[(tert-butoxycarbonyl)amino]-l,3-benzothiazol-6-yl}oxy)- 4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl]oxy}-l,3-benzothiazol-7-yl)carbamate (1.4 g, 83%) as a colorless crystal. C50H76Br2N4O15S2: MW 1197. LC-MS (ESI, m / z): [M + H]+ = 1195, 1197. 1H NMR (400 MHz, CDC13) 5 7.72 - 7.63 (m, 2H), 7.13 - 7.07 (m, 4H), 4.21 (t, J = 6.3 Hz, 4H), 3.67 - 3.42 (m, 36H), 2.13 - 2.06 (m, 4H), 1.88 - 1.79 (m, 8H), 1.55 (s, 18H).

[0250] Step 8: Tert-butyl N-(2-bromo-6-{[35-({2-bromo-7-[(tert-butoxycarbonyl)(ethyl)amino]-1.3-benzothiazol-6-yl}oxy)-4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl]oxy}-l,3- benzothiazol-7-yl)-N-ethylcarbamate. To a stirred solution of tert-butyl N-(2-bromo-6-{[35-({2- bromo-7-[(tert-butoxycarbonyl)amino]-l,3-benzothiazol-6-yl}oxy)-4,8,12,15,18,21,24,28,32- nonaoxapentatriacontan-l-yl]oxy}-l,3-benzothiazol-7-yl)carbamate (650 mg, 0.543 mmol, 1 equiv.) in DMF (6 mL) was added NaH (54.3 mg, 1.36 mmol, 2.5 equiv., 60%) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added ethyl iodide (212 mg, 1.36 mmol, 2.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred for an additional 2 h at room temperature. The reaction was monitored by LCMS. The reaction was quenched with sat. NH4CI (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL), the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford tert-butyl N-(2-bromo-6-{[35-({2-bromo-7-[(tert- butoxycarbonyl)(ethyl)amino]-l,3-benzothiazol-6-yl}oxy)-4,8,12,15,18,21,24,28,32- nonaoxapentatriacontan-l-yl]oxy}-l,3-benzothiazol-7-yl)-N-ethylcarbamate (600 mg, 88%) as a colorless oil. C54H84Br2N4O15S2: MW 1253. LC-MS (ESI, m / z): [M + H]+ = 1251, 1253.

[0251] Step 9: Tert-butyl N-(6-{[35-({7-[(tert-butoxycarbonyl)(ethyl)amino]-2-sulfamoyl-l,3- benzothiazol-6-yl}oxy)-4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl]oxy}-2- sulfamoyl-l,3-benzothiazol-7-yl)-N-ethylcarbamate. To a stirred solution of tert-butyl N-(2-WSGR Docket No. 20012-705.601 bromo-6-{[35-({2-bromo-7-[(tert-butoxycarbonyl)(ethyl)amino]-l,3-benzothiazol-6-yl}oxy)- 4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl]oxy}-l,3-benzothiazol-7-yl)-N- ethylcarbamate (500 mg, 0.399 mmol, 1 equiv.) in THF (5 mL) was added chloro(isopropyl)magnesium (246 mg, 2.39 mmol, 6 equiv.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. To the above mixture was added tert-butoxy(sulfinylidene)amine (324 mg, 2.39 mmol, 6 equiv.) dropwise at -78 °C. The resulting mixture was stirred for an additional 5 h at room temperature. The reaction was monitored by LCMS. The reaction was quenched with water (1 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford tert-butyl N-(6-{[35-({7-[(tert-butoxycarbonyl)(ethyl)amino]-2-sulfamoyl-l,3-benzothiazol-6- yl}oxy)-4,8,12,15,18,21,24,28,32-nonaoxapentatriacontan-l-yl]oxy}-2-sulfamoyl-l,3- benzothiazol-7-yl)-N-ethylcarbamate (54.5 mg, 11%) as a white semi-solid. C54H88N6O19S4: MW 1254. LC-MS (ESI, m / z): [M + H]+ = 1254. 1H NMR (400 MHz, DMSO-d6) 5 8.31 (d, J = 9.9 Hz, 4H), 8.09 (dd, J = 9.1, 2.7 Hz, 2H), 7.51 (d, J = 9.1 Hz, 2H), 4.21 (q, J = 4.7 Hz, 4H), 3.76 - 3.62 (m, 2H), 3.58 - 3.29 (m, 38H), 2.04 - 1.91 (m, 4H), 1.77 - 1.63 (m, 8H), 1.49 (s, 6H), 1.22 (s, 12H), 1.07 (t, J = 7.1 Hz, 2H), 1.00 (t, J = 7.1 Hz, 4H).Example 17, 7-(3-isopropyl-2-oxotetrahvdropyrimidin-l(2H)-yl)-6-(3- methoxypropoxy)benzord1thiazole-2-sulfonamide

[0252] Step 1 : tert-butyl N-(3-hydroxypropyl)-N-isopropylcarbamate. To a stirred mixture of 3- (isopropylamino)propan-l-ol (2.5 g, 21 mmol, 1 equiv.) and di-tert-butyl decarbonate (6.98 g, 32.0 mmol, 1.5 equiv.) in DCM (50 mL) was added TEA (5.93 mL, 42.7 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford tert-butyl N-(3- hydroxypropyl)-N-isopropylcarbamate (3.7 g, 80%) as a yellow oil. C11H23NO3: MW 217.WSGR Docket No. 20012-705.601LC-MS (ESI, m / z): [M + H]+ = 218. 1H NMR (400 MHz, Chloroform-d) 5 3.97 (s, 1H), 3.58 (s, 2H), 3.33 (s, 2H), 1.68 (s, 2H), 1.47 (s, 9H), 1.16 (d, J = 6.8 Hz, 6H).

[0253] Step 2 : tert-butyl N-isopropyl-N-(3-oxopropyl)carbamate. To a stirred solution of tertbutyl N-(3-hydroxypropyl)-N-isopropylcarbamate (2.5 g, 11.504 mmol, 1 equiv.) in DCM (30 mL) was added Dess-Martin (5.86 g, 13.8 mmol, 1.2 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with sat. sodium hyposulfite (aq., 100 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 100 mL). The organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 40%) to afford tertbutyl N-isopropyl-N-(3-oxopropyl)carbamate (1.8 g) as a yellow oil. Cl 1H21NO3: MW 215. LC-MS (ESI, m / z): [M + H]+ = 216.

[0254] Step 3 : tert-butyl N-(3-{ [2-bromo-6-(3 -methoxypropoxy)- 1, 3-benzothiazol-7- yl]amino}propyl)-N-isopropylcarbamate. To a stirred mixture of tert-butyl N-isopropyl-N-(3- oxopropyl)carbamate (1.6 g, 7.432 mmol, 1.00 equiv.) and 2-bromo-6-(3 -methoxypropoxy)- 1,3- benzothiazol-7-amine (1.89 g, 5.96 mmol, 0.80 equiv.) in DCE (20 mL) was added DIEA (1.29 mL, 7.43 mmol, 1 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. To the above mixture was added STAB (3.15 g, 14.9 mmol, 2 equiv.) in portions at room temperature. The resulting mixture was stirred for an additional 5 h at 50 °C. The desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (5 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30% - 40%) to afford tert-butyl N-(3-{ [2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7-yl]amino}propyl)- N-isopropylcarbamate (1.2 g, 31%) as a yellow oil. C22H34BrN3O4S: MW 516. LC-MS (ESI, m / z): [M + H]+ = 516, 518. 1H NMR (300 MHz, Chloroform-d) 5 7.43 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 4.17 (t, J = 6.2 Hz, 2H), 4.12 - 3.90 (m, 1H), 3.59 (t, J = 6.0 Hz, 2H), 3.40 (t, J = 6.7 Hz, 2H), 3.36 (s, 3H), 3.21 (s, 2H), 2.18 - 2.04 (m, 2H), 1.83 - 1.68 (m, 2H), 1.46 (s, 9H), 1.11 (d, J = 6.8 Hz, 6H).

[0255] Step 4: 2-Bromo-N-[3-(isopropylamino)propyl]-6-(3-methoxypropoxy)-l,3- benzothiazol-7-amine. To a stirred solution of tert-butyl N-(3-{[2-bromo-6-(3- methoxypropoxy)-l,3-benzothiazol-7-yl]amino}propyl)-N-isopropylcarbamate (1.2 g, 2.32 mmol, 1 equiv.) in DCM (7 mL) was added TFA (3 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixtureWSGR Docket No. 20012-705.601 was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% TFA, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 2-bromo-N-[3- (isopropylamino)propyl]-6-(3-methoxypropoxy)-l,3-benzothiazol-7-amine (900 mg, 93%) as a yellow solid. C17H26BrN3O2S: MW 416. LC-MS (ESI, m / z): [M + H]+ = 416, 418. 1H NMR (300 MHz, Chloroform-d) 5 7.44 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.15 (t, J = 6.4 Hz, 2H), 3.56 (t, J = 5.9 Hz, 2H), 3.45 (t, J = 6.3 Hz, 2H), 3.35 (s, 3H), 3.33 - 3.26 (m, 1H), 3.14 - 3.04 (m, 2H), 2.16 - 1.98 (m, 4H), 1.35 (d, J = 6.6 Hz, 6H).

[0256] Step 5: l-[2-Bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7-yl]-3-isopropyl-l,3- diazinan-2-one. To a stirred mixture of 2-bromo-N-[3-(isopropylamino)propyl]-6-(3- methoxypropoxy)-l,3-benzothiazol-7-amine (400 mg, 0.961 mmol, 1 equiv.) and DIEA (0.50 mL, 2.88 mmol, 3 equiv.) in DCM (8 mL) was added triphosgene (85 mg, 0.288 mmol, 0.3 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 6 h at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / methanol (5% - 10%) to afford l-[2-bromo-6-(3-methoxypropoxy)-l,3-benzothiazol-7-yl]-3-isopropyl-l,3-diazinan-2- one (270 mg, 64%) as a yellow solid. C18H24BrN3O3S: MW 442. LC-MS (ESI, m / z): [M + H]+ = 442, 444. 1H NMR (400 MHz, DMSO-d6) 5 7.86 (d, J = 8.9 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 4.57 - 4.45 (m, 1H), 4.13 (t, J = 6.1 Hz, 2H), 3.56 - 3.45 (m, 3H), 3.34 - 3.26 (m, 3H), 3.24 (s, 3H), 2.10 - 1.90 (m, 4H), 1.09 (t, J = 6.9 Hz, 6H).

[0257] Step 6: 7-(3-Isopropyl-2-oxo-l,3-diazinan-l-yl)-6-(3-methoxypropoxy)-l,3- benzothiazole-2-sulfonamide. To a stirred solution of l-[2-bromo-6-(3 -methoxypropoxy)- 1,3- benzothiazol-7-yl]-3-isopropyl-l,3-diazinan-2-one (200 mg, 0.452 mmol, 1 equiv.) in THF (4 mL) was added i-PrMgBr (1.36 mL, 1.36 mmol, 3 equiv.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. To the above mixture was added tert-butoxy(sulfinylidene)amine (183 mg, 1.36 mmol, 3 equiv.) dropwise at -78 °C. The resulting mixture was stirred for an additional 12 h at room temperature. The desired product could be detected by LCMS. The reaction was quenched with water (5 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 7-(3-isopropyl-2-oxo-l,3-diazinan-l-yl)-6-(3-methoxypropoxy)-l,3-WSGR Docket No. 20012-705.601 benzothiazole-2-sulfonamide (80 mg, 40%) as a white solid. C18H26N4O5S2: MW 442. LC- MS (ESI, m / z): [M + H]+ = 443. 1H NMR (400 MHz, DMSO-d6) 5 8.26 (s, 2H), 8.03 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.18 (t, J = 6.1 Hz, 2H), 3.60 - 3.46 (m, 3H), 3.42 - 3.34 (m, 1H), 3.31 - 3.26 (m, 2H), 3.24 (s, 3H), 2.09 - 1.92 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H).Example 18, 7-(3,5-dimethylphenyl)-6-(3-methoxypropoxy)benzo[d1thiazole-2- sulfonamide

[0258] Step 1 : 2-Bromo-l,3-benzothiazol-6-ol. To a stirred solution of 2-bromo-6-methoxy-l,3- benzothiazole (10.5 g, 43.0 mmol, 1 equiv.) in DCM (150 mL) was added boron tribromide (21.55 g, 86.0 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred overnight at 40 °C. The desired product could be detected by LCMS. The reaction was quenched with water (1000 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (4 x 1 L). The combined organic layers were washed with water (3 x 500 mL) and brine (3 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-bromo-l,3-benzothiazol-6-ol (10.4 g, 100%) as a brown solid. C7H4BrNOS: MW 230. LC-MS (ESI, m / z): [M + H]+ = 230, 232. 1H NMR (300 MHz, DMSO-d6) 5 9.99 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.03 - 6.94 (m, 1H).

[0259] Step 2: 2-Bromo-7-iodo-l,3-benzothiazol-6-ol. To a stirred solution of 2-bromo-l,3- benzothiazol-6-ol (10.4 g, 45.2 mmol, 1 equiv.) in DMF (100 mL) was added N- iodosuccinimide (10.17 g, 45.2 mmol, 1 equiv.) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The desired product could be detected by LCMS. The resulting mixture was diluted with water (1 L). The resulting mixture was extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with water (3 x 500 mL) and brine (3 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30% - 60%) to afford 2-bromo-7-iodo-l,3-benzothiazol-6-ol (11.6 g, 72%) as a yellow solid. C7H3BrINOS: MW 356. LC-MS (ESI, m / z): [M + H]+ = 356, 358. 1H NMR (300 MHz, DMSO-d6) 5 10.90 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H).

[0260] Step 3: 2-Bromo-7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole. To a stirred solution of 2-bromo-7-iodo-l,3-benzothiazol-6-ol (11.6 g, 32.6 mmol, 1 equiv.) and l-bromo-3- methoxypropane (7.48 g, 48.9 mmol, 1.5 equiv.) in DMF (100 mL) was added K2CO3 (9.01 g, 65.2 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture wasWSGR Docket No. 20012-705.601 stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30% - 60%) to afford 2-bromo-7-iodo-6-(3- methoxypropoxy)-l,3-benzothiazole (10 g, 72%) as a yellow solid. Cl 1H1 lBrINO2S: MW 428. LC-MS (ESI, m / z): [M + H]+ = 428, 430. 1H NMR (300 MHz, DMSO-d6) 5 7.93 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 4.17 (t, J = 6.1 Hz, 2H), 3.55 (t, J = 6.3 Hz, 2H), 3.26 (s, 3H), 2.03 - 1.94 (m, 2H).

[0261] Step 4: 2-Bromo-7-(3,5-dimethylphenyl)-6-(3-methoxypropoxy)-l,3-benzothiazole. To a stirred solution of 2-bromo-7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole (553 mg, 1.29 mmol, 1 equiv.) and 2-(3,5-dimethylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (300 mg, 1.29 mmol, 1 equiv.) in 1,4-dioxane (3 mL) and H2O (50 mL) were added Pd(dppf)C12-CH2C12 (105 mg, 0.129 mmol, 0.1 equiv.) and K2CO3 (536 mg, 3.88 mmol, 3 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The reaction mixture was allowed to cool down to room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: C18, 120 g; Mobile Phase A: Water / 0.1% FA, Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 5% B to 5% B in 5 min, 5% B to 60% B in 10 min, 60% B to 95% B in 30 min, 95% B to 95% B in 4 min; Wave Length: 254 / 220 nm) to afford 2- bromo-7-(3,5-dimethylphenyl)-6-(3-methoxypropoxy)-l,3-benzothiazole (85 mg, 16%) as a white solid. C19H20BrNO2S: MW 406. LC-MS (ESI, m / z): [M + H]+ = 406, 408. 1H NMR (300 MHz, Chloroform-d) 5 7.85 (d, J = 8.9 Hz, 1H), 7.18 (dd, J = 8.9, 2.7 Hz, 1H), 7.13 (s, 2H), 7.03 (s, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.42 (t, J = 6.2 Hz, 2H), 3.30 (s, 3H), 2.37 (s, 6H), 2.03 - 1.88 (m, 2H).

[0262] Step 5: 7-(3,5-Dimethylphenyl)-6-(3-methoxypropoxy)-l,3-benzothiazole-2- sulfonamide. To a stirred solution of 2-bromo-7-(3,5-dimethylphenyl)-6-(3-methoxypropoxy)- 1,3 -benzothiazole (83 mg, 0.20 mmol, 1 equiv.) in THF (5 mL) was added i-PrMgCl (84 mg, 0.82 mmol, 4 equiv.) dropwise at -40 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. To the above mixture was added / c / 7- butoxy(sulfmylidene)amine (83 mg, 0.61 mmol, 3 equiv.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Cl 8, 120 g; MobileWSGR Docket No. 20012-705.601Phase A: Water / 0.1% FA, Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 5% B to 5% B in 5 min, 5% B to 40% B in 8 min, 40% B to 70% B in 20 min, 70% B to 95% B in 1 min, 95% B to 95% B in 4 min; Wave Length: 254 / 220 nm) to afford 7-(3,5-dimethylphenyl)-6-(3- methoxypropoxy)-l,3-benzothiazole-2-sulfonamide (26 mg, 31%) as a white solid. C19H22N2O4S2: MW 407. LC-MS (ESI, m / z): [M + H]+ = 407. 1H NMR (300 MHz, DMSO- d6) 5 8.26 (s, 2H), 8.11 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.14 (s, 2H), 7.09 (s, 1H), 4.15 (t, J = 6.1 Hz, 2H), 3.45 - 3.35 (m, 2H), 3.20 (s, 3H), 2.34 (s, 6H), 1.92 - 1.80 (m, 2H).Example 19, 7-iodo-6-(3-methoxypropoxy)benzord]thiazole-2-sulfonamide

[0263] Step 1 : 2-Bromo-7-iodo-l,3-benzothiazol-6-ol. To a stirred solution of 2-bromo-l,3- benzothiazol-6-ol (9.2 g, 40 mmol, 1 equiv.) in DMF (100 mL) was added NIS (9.00 g, 40.0 mmol, 1 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 30%) to afford 2-bromo-7-iodo-l,3-benzothiazol-6-ol (14 g, 79%) as a brown solid. C7H3BrINOS: MW 356. LC-MS (ESI, m / z): [M + H]+ = 356, 358.

[0264] Step 2: 2-Bromo-7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole. To a stirred solution of 2-bromo-7-iodo-l,3-benzothiazol-6-ol (12 g, 34 mmol, 1 equiv.) and l-bromo-3- methoxypropane (7.74 g, 50.5 mmol, 1.50 equiv.) in DMF (100 mL) was added K2CO3 (9.32 g, 67.4 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 30%) to afford 2-bromo-7- iodo-6-(3 -methoxypropoxy)- 1,3 -benzothiazole (10 g, 69%) as a yellow solid. Cl 1H1 lBrINO2S: MW 428. LC-MS (ESI, m / z): [M + H]+ = 428, 430. 1H NMR (400 MHz, Chloroform-d) 5 7.87 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 4.20 (t, J = 6.1 Hz, 2H), 3.64 (t, J = 6.1 Hz, 2H), 3.37 (s, 3H), 2.17 - 2.08 (m, 2H).WSGR Docket No. 20012-705.601

[0265] Step 3: 7-Iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2-thiol. To a stirred solution of 2-bromo-7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole (600 mg, 1.40 mmol, 1 equiv.) in EtOH (10 mL) was added sodium hydrosulfide (0.39 g, 7.0 mmol, 5 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (50% - 60%) to afford 7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2 -thiol (510 mg, 95%) as a white solid. Cl 1H12INO2S2: MW 381. LC-MS (ESI, m / z): [M + H]+ = 382. 1H NMR (400 MHz, DMSO-d6) 5 13.95 (s, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.12 (t, J = 6.2 Hz, 2H), 3.56 (t, J = 6.3 Hz, 2H), 3.28 (s, 3H), 2.01 - 1.95 (m, 2H).

[0266] Step 4. {[7-Iodo-6-(3-methoxypropoxy)-l,3-benzothiazol-2-yl]sulfanyl}amine. To a stirred solution of aqueous ammonia (6.00 mL, 38.5 mmol, 29 equiv., 25%) was added NaClO (3.00 mL, 44.3 mmol, 34 equiv.) dropwise at -5 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at -5 °C under nitrogen atmosphere. To the above mixture were added 7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2 -thiol (500 mg, 1.31 mmol, 1 equiv.) and NaOH (6.00 mL, 3.0 M) dropwise at -5 °C. The resulting mixture was stirred for an additional 1 h at -5 °C. The desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with water (4 mL). This resulted in {[7-iodo-6-(3- methoxypropoxy)-l,3-benzothiazol-2-yl]sulfanyl}amine (500 mg, 96%) as a white solid.Cl 1H13IN2O2S2: MW 396. LC-MS (ESI, m / z): [M + H]+ = 397.

[0267] Step 5: 7-Iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2-sulfonamide. To a stirred mixture of {[7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazol-2-yl]sulfanyl}amine (500 mg, 1.26 mmol, 1 equiv.) in DCM (5 mL) was added mCPBA (653 mg, 3.79 mmol, 3 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. sodium hyposulfite (aq.) at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Cl 8, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 7-iodo-6-(3- methoxypropoxy)-l,3-benzothiazole-2-sulfonamide (300 mg, 56%) as a white solid.Cl 1H13IN2O4S2: MW 428. LC-MS (ESI, m / z): [M + H]+ = 429. 1H NMR (400 MHz, DMSO- d6) 5 8.33 (s, 2H), 8.15 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 4.24 (t, J = 6.1 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.05 - 1.97 (m, 2H).WSGR Docket No. 20012-705.601Example 20, 6-(3-methoxypropoxy)-7-phenylbenzord1thiazole-2-sulfonamide

[0268] Step 1 : 6-(3-Methoxypropoxy)-7-phenyl-l,3-benzothiazole-2-sulfonamide. To a stirred mixture of 7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2-sulfonamide (100 mg, 0.234 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-2-phenyl-l,3,2-dioxaborolane (47.7 mg, 0.234 mmol, 1 equiv.) in dioxane (1 mL) and H2O (0.2 mL) were added K2CO3 (96.8 mg, 0.702 mmol, 3 equiv.) and Pd(dppf)C12.CH2C12 (19.0 mg, 0.023 mmol, 0.1 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Cl 8, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 6-(3-methoxypropoxy)-7-phenyl-l,3-benzothiazole-2- sulfonamide (23 mg, 26%) as a white solid. C17H18N2O4S2: MW 378. LC-MS (ESI, m / z): [M + H]+ = 379. 1H NMR (400 MHz, DMSO-d6) 5 8.21 (s, 2H), 8.13 (d, J = 9.0 Hz, 1H), 7.61 - 7.50 (m, 5H), 7.49 - 7.43 (m, 1H), 4.16 (t, J = 6.2 Hz, 2H), 3.35 - 3.32 (m, 2H), 3.18 (s, 3H), 1.90 - 1.80 (m, 2H).Using the above procedure, the following examples in Table 3 were prepared.Table 3WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601Example 87, tert-butyl propyl(2-sulfamoylbenzord1thiazol-7-yl)carbamate

[0269] Step 1 : Methyl 2-bromo-l,3-benzothiazole-7-carboxylate. To a stirred mixture of cupric bromide (6.73 g, 30.1 mmol, 1.65 equiv.) and tert-butyl nitrite (3.29 g, 31.9 mmol, 1.8 equiv.) in dry ACN (30 mL) was added methyl 2-amino-l,3-benzothiazole-7-carboxylate (3.8 g, 18 mmol, 1 equiv.) in portions over 5 min at room temperature. The resulting mixture was stirred for 6 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with ethyl acetate (250 mL), quenched with 1 N HC1 (50 mL). The resulting mixture was washed with water (200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0% - 50%) to afford methyl 2-bromo- l,3-benzothiazole-7-carboxylate (3.8 g, 77%) as a white solid. C9H6BrNO2S: MW 272. LC-MSWSGR Docket No. 20012-705.601(ESI, m / z): [M + H]+ = 272, 274. 1H NMR (400 MHz, Chloroform-d) 5 8.18 (dd, J = 8.0, 1.2 Hz, 1H), 8.12 (dd, J = 7.6, 1.2 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 4.03 (s, 3H).

[0270] Step 2: 2-Bromo-l,3-benzothiazole-7-carboxylic acid. A solution of methyl 2-bromo- l,3-benzothiazole-7-carboxylate (4.7 g, 17 mmol, 1 equiv.) in THF (100 mL) were added LiOH H2O (2.17 g, 51.8 mmol, 3 equiv.) and H2O (30 mL) at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The reaction was monitored by LCMS. The mixture was diluted with ethyl acetate (200 mL), and acidified to pH 3 with 1 N HC1 aqueous solution. The organic layer was collected, washed with brine, dried over Na2SO4. The organic layer was concentrated under reduced pressure to afford 2-bromo-l,3-benzothiazole-7-carboxylic acid (4.3 g, 96%) as white solid. C8H4BrNO2S: MW 258. LC-MS (ESI, m / z): [M - H]- = 256, 258. 1H NMR (400 MHz, DMSO-d6) 5 8.26 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H).

[0271] Step 3: tert-butyl N-(2 -bromo- l,3-benzothiazol-7-yl)carbamate. To a suspension of 2- bromo-l,3-benzothiazole-7-carboxylic acid (2 g, 7.749 mmol, 1 equiv.) in dry toluene (60 mL) were added TEA (2.35 g, 23.2 mmol, 3 equiv.), DPPA (2.56 g, 9.30 mmol, 1.2 equiv.) and tertbutanol (0.039 mL, 0.40 mmol) at room temperature. The reaction mixture was heated at 80 °C for overnight. The reaction was monitored by LCMS. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0% - 30%) to afford tert-butyl N-(2-bromo-l,3-benzothiazol-7-yl)carbamate (900 mg, 35%) as a white solid. C12H13BrN2O2S: MW 329. LC-MS (ESI, m / z): [M + H]+ = 329, 331. 1H NMR (400 MHz, Chloroform-d) 5 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 - 7.39 (m, 2H), 6.50 (s, 1H), 1.55 (s, 9H).

[0272] Step 4: tert-butyl N-(2 -bromo- l,3-benzothiazol-7-yl)-N-propylcarbamate. To a stirred solution of tert-butyl N-(2-bromo-l,3-benzothiazol-7-yl)carbamate (150 mg, 0.456 mmol, 1 equiv.) in DMF (2 mL) was added NaH (23 mg, 0.59 mmol, 1.3 equiv., 60%) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 0.5 h at 0 °C. To the above mixture was added iodopropane (101 mg, 0.593 mmol, 1.3 equiv.) dropwise over 10 min at 0 °C. The resulting mixture was stirred for an additional 2 h at room temperature. The desired product could be detected by LCMS. The reaction was quenched by the addition of water (2 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0% - 20%) to afford tertbutyl N-(2-bromo-l,3-benzothiazol-7-yl)-N-propylcarbamate (160 mg, 95%) as a white solid. C15H19BrN2O2S: MW 371. LC-MS (ESI, m / z): [M + H]+ = 371, 373. 1H NMR (300 MHz, Chloroform-d) 5 7.88 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.23 (s, 1H), 3.64 (t, J = 7.6 Hz, 2H), 1.57 - 1.21 (m, 11H), 0.88 (t, J = 7.4 Hz, 3H).WSGR Docket No. 20012-705.601

[0273] Step 5: tert-butyl N-propyl-N-(2-sulfamoyl-l,3-benzothiazol-7-yl)carbamate. To a stirred solution of tert-butyl N-(2-bromo-l,3-benzothiazol-7-yl)-N-propylcarbamate (140 mg, 0.377 mmol, 1 equiv.) in THF (3 mL) was added i-PrMgCl (116 mg, 1.13 mmol, 3 equiv.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. To the above mixture was added tert- butoxy(sulfmylidene)amine (153 mg, 1.13 mmol, 3 equiv.) dropwise over 5 min at -78 °C. The resulting mixture was stirred for an additional overnight at room temperature. The desired product could be detected by LCMS. The reaction was quenched by the addition of water (10 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Cl 8, 80 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 4 min; 5% B to 95% B in 30 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford tert-butyl N-propyl-N-(2-sulfamoyl-l,3-benzothiazol-7-yl)carbamate (59 mg, 40%) as a white solid. C15H21N3O4S2: MW 371. LC-MS (ESI, m / z): [M - H]- = 370. 1H NMR (400 MHz, DMSO-d6) 5 8.42 (s, 2H), 8.11 (dd, J = 8.2, 1.0 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.60 (dd, J = 7.7, 1.0 Hz, 1H), 3.67 (t, J = 7.2 Hz, 2H), 1.58 - 1.19 (m, 11H), 0.83 (t, J = 7.4 Hz, 3H).Example 88, 7-(l-(tert-butyl)-lH-indazol-3-yl)-6-(3-methoxypropoxy)benzo[d]thiazole- 2-sulfonamide

[0274] Step 1 : 2-Bromo-7-iodo-l,3-benzothiazol-6-ol. To a stirred solution of 2-bromo-l,3- benzothiazol-6-ol (9.20 g, 40.0 mmol, 1 equiv.) in DMF (100 mL) was added NIS (9.00 g, 40.0 mmol, 1 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 30%) to afford 2-bromo-7-iodo-l,3-benzothiazol-6-ol (14 g, 79%) as a brown solid. C7H3BrINOS: MW 356. LC-MS (ESI, m / z): [M + H]+ = 356, 358.

[0275] Step 2: 2-Bromo-7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole. To a stirred solution of 2-bromo-7-iodo-l,3-benzothiazol-6-ol (12 g, 33 mmol, 1 equiv.) and l-bromo-3-WSGR Docket No. 20012-705.601 methoxypropane (7.74 g, 50.6 mmol, 1.5 equiv.) in DMF (100 mL) was added K2CO3 (9.32 g, 67.4 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% - 30%) to afford 2- bromo-7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole (10 g, 69%) as a yellow solid. Cl lHl lBrINO2S: MW 428. LC-MS (ESI, m / z): [M + H]+ = 428, 430. 1H NMR (400 MHz, Chloroform-d) 5 7.87 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 4.20 (t, J = 6.1 Hz, 2H), 3.64 (t, J = 6.1 Hz, 2H), 3.37 (s, 3H), 2.17 - 2.08 (m, 2H).

[0276] Step 3: 7-Iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2-thiol. To a stirred solution of 2-bromo-7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole (600 mg, 1.40 mmol, 1 equiv.) in EtOH (10 mL) was added sodium hydrosulfide (0.39 g, 7.0 mmol, 5 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (50% - 60%) to afford 7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2 -thiol (510 mg, 95%) as a white solid. Cl 1H12INO2S2: MW 381. LC-MS (ESI, m / z): [M + H]+ = 382. 1H NMR (400 MHz, DMSO-d6) 5 13.95 (s, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.12 (t, J = 6.2 Hz, 2H), 3.56 (t, J = 6.3 Hz, 2H), 3.28 (s, 3H), 2.01 - 1.95 (m, 2H).

[0277] Step 4. {[7-Iodo-6-(3-methoxypropoxy)-l,3-benzothiazol-2-yl]sulfanyl}amine. To a stirred solution of aqueous ammonia (6.00 mL, 38.5 mmol, 29.4 equiv., 25%) was added NaClO (3.00 mL, 44.3 mmol, 34 equiv.) dropwise at -5 °C under nitrogen atmosphere. The resulting mixture was stirred for 10 min at -5 °C under nitrogen atmosphere. To the above mixture were added 7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2 -thiol (500 mg, 1.31 mmol, 1 equiv.) and NaOH (6.00 mL, 3.0 M) dropwise at -5 °C. The resulting mixture was stirred for an additional 1 h at -5 °C. The desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with water (4 mL). This resulted in {[7-iodo-6-(3- methoxypropoxy)-l,3-benzothiazol-2-yl]sulfanyl}amine (500 mg, 96%) as a white solid.Cl 1H13IN2O2S2: MW 396. LC-MS (ESI, m / z): [M + H]+ = 397.

[0278] Step 5: 7-Iodo-6-(3-methoxypropoxy)-l,3-benzothiazole-2-sulfonamide. To a stirred mixture of {[7-iodo-6-(3-methoxypropoxy)-l,3-benzothiazol-2-yl]sulfanyl}amine (500 mg, 1.26WSGR Docket No. 20012-705.601 mmol, 1 equiv.) in DCM (5 mL) was added mCPBA (653 mg, 3.79 mmol, 3 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with sat. sodium hyposulfite at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Cl 8, 120 g; Mobile Phase A: Water / 0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 70 mL / min; Gradient: 5% B to 5% B in 3 min; 5% B to 95% B in 25 min; 95% B to 95% B in 10 min; Detector, 254 / 220 nm) to afford 7-iodo-6-(3- methoxypropoxy)-l,3-benzothiazole-2-sulfonamide (300 mg, 56%) as a white solid.Cl 1H13IN2O4S2: MW 428. LC-MS (ESI, m / z): [M + H]+ = 429. 1H NMR (400 MHz, DMSO- d6) 5 8.33 (s, 2H), 8.15 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 4.24 (t, J = 6.1 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.27 (s, 3H), 2.05 - 1.97 (m, 2H).

[0279] Step 6: N’-tert-butyl-2-iodobenzohydrazide. To a stirred mixture of 2-iodobenzoic acid (1 g, 4.032 mmol, 1 equiv.), Zc / V-butyl hydrazine (355 mg, 4.03 mmol, 1 equiv.), EDCI (1159 mg, 6.05 mmol, 1.5 equiv.) and HOBT (817 mg, 6.05 mmol, 1.5 equiv.) in DMF (10 mL) was added DMAP (49 mg, 0.40 mmol, 0.1 equiv.) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was purified by reverse flash chromatography with the following conditions (Column: Cl 8, 80 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 5% B to 5% B in 5 min; 5% B to 50% B in 30 min; 50% B to 95% B in 5 min; Detector, 254 / 220 nm) to afford N’- tert-butyl-2-iodobenzohydrazide (530 mg, 41%) as a white oil. C11H15IN2O: MW 318. LC-MS (ESI, m / z): 319 [M + H]+; 1H NMR (400 MHz, Chloroform-d) 5 7.89 (d, J = 7.9 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.17 - 7.09 (m, 1H), 6.13 (s, 2H), 1.22 (s, 9H).

[0280] Step 7: l-tert-butyl-2H-indazol-3-one. To a stirred mixture of N’-tert-butyl-2- iodobenzohydrazide (500 mg, 1.57 mmol, 1 equiv.), L-proline (90 mg, 0.79 mmol, 0.5 equiv.) and K2CO3 (652 mg, 4.72 mmol, 3 equiv.) in DMSO (5 mL) was added Cui (75 mg, 0.39 mmol, 0.25 equiv.) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was purified by reverse flash chromatography with the following conditions (Column: Cl 8, 80 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 5% B to 5% B in 5 min; 5% B to 50% B in 30 min; 50% B to 95% B in 5 min; Detector, 254 / 220 nm) to afford l-tert-butyl-2H-indazol-3-one (220 mg, 74%) as a yellow solid. C11H14N2O: MW 190. LC-MS (ESI, m / z): 191 [M + H]+; lH NMR (300WSGR Docket No. 20012-705.601MHz, Chloroform-d) 5 9.21 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 1.69 (s, 9H).

[0281] Step 8: 3-Bromo-l-tert-butylindazole. To a stirred mixture of l-tert-butyl-2H-indazol-3- one (200 mg, 1.05 mmol, 1 equiv.) in toluene (2 mL) was added POBr3 (904 mg, 3.15 mmol, 3 equiv.) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0%-30%) to afford 3 -bromo- 1 -tert-butyl indazole (120 mg, 45%) as a yellow solid. Cl lH13BrN2: MW 253. LC-MS (ESI, m / z): 253, 255 [M + H]+; 1H NMR (400 MHz, Chloroform-d) 5 7.66 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.37 (ddd, J = 8.5, 6.9, 1.2 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 1.77 (s, 9H).

[0282] Step 9: l-tert-butyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole. To a stirred mixture of 3-bromo-l-tert-butylindazole (120 mg, 0.474 mmol, 1 equiv.), bis(pinacolato)diboron (241 mg, 0.948 mmol and 2 equiv.), KO Ac (140 mg, 1.42 mmol, 3 equiv.) in dioxane (1 mL) was added Pd(dppf)C12.CH2C12 (39 mg, 0.047 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude was used in the next step directly without further purification. C17H25BN2O2: MW 300. LC-MS (ESI, m / z): 301 [M + H]+.

[0283] Step 10: 7-(l-tert-butylindazol-3-yl)-6-(3-methoxypropoxy)-l,3-benzothiazole-2- sulfonamide. To a stirred mixture of l-tert-butyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) indazole (190 mg, 0.633 mmol, 1 equiv.), 7-iodo-6-(3-methoxypropoxy)benzo[d]thiazole-2- sulfonamide (157 mg, 0.466 mmol, 1 equiv.) and K2CO3 (262 mg, 1.90 mmol, 3 equiv.) in dioxane (1 mL) and H2O (0.2 mL) was added Pd(dppf)C12.CH2C12 (52 mg, 0.063 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions (Column: Cl 8, 80 g; Mobile Phase A: Water / 0.05% FA, Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 5% B to 5% B in 5 min; 5% B to 50% B in 30 min; 50% B to 95% B in 5 min; Detector, 254 / 220 nm) to 7-(l-tert- butylindazol-3-yl)-6-(3 -methoxypropoxy)- 1, 3 -benzothiazole-2-sulfonamide (25 mg, 8%) as a white solid. C22H26N4O4S2: MW 475. LC-MS (ESI, m / z): 475 [M + H]+; 1H NMR (400 MHz, DMSO-d6) 5 8.23 (s, 2H), 8.17 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.43 (ddd, J = 8.5, 6.8, 1.2 Hz, 1H), 7.20 (t, J = 7.4 Hz,WSGR Docket No. 20012-705.6011H), 4.29 (t, J = 6.5 Hz, 2H), 3.30 (t, J = 6.3 Hz, 2H), 3.13 (s, 3H), 1.97 - 1.86 (m, 2H), 1.83 (s, 9H).Example 89, tert-butyl (2 -methoxy ethyl)(2-sulfamoylbenzord]thiazol-7-yl)carbamatetert- butyl (2-methoxyethyl)(2-sulfarnoylbenzo[d]thiazol-7-yl)carbamate

[0284] Step 1 : tert-butyl N-(2-bromo-l,3-benzothiazol-7-yl)-N-(2-methoxyethyl)carbamate. To a solution of tert-butyl N-(2-bromo-l,3-benzothiazol-7-yl)carbamate (200 mg, 0.608 mmol, 1 equiv.) in dry DMF (3 mL) was added NaH (29 mg, 0.73 mmol, 1.2 equiv., 60%) at 0 °C. The mixture was stirred for 30 min. l-Iodo-2-m ethoxy ethane (136 mg, 0.730 mmol, 1.2 equiv.) was added to the above mixture. The reaction mixture was allowed to warm to 80 °C and stirred for an additional 2 h. The desired product could be detected by LCMS. The reaction mixture was quenched by sat. NH4CI (50 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0% - 30%) to afford tert-butyl N-(2- bromo-l,3-benzothiazol-7-yl)-N-(2-methoxyethyl)carbamate (180 mg, 77%) as a colorless oil. C15H19BrN2O3S: MW 387. LC-MS (ESI, m / z): [M + H]+ = 387, 389. 1H NMR (400 MHz, Chloroform-d) 5 7.88 (dd, J = 8.1, 1.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.29 (br, s, 1H), 3.86 (t, J = 5.7 Hz, 2H), 3.46 (t, J = 5.7 Hz, 2H), 3.27 (s, 3H), 1.34 (br, s, 9H).

[0285] Step 2: tert-butyl N-(2-methoxyethyl)-N-(2-sulfamoyl-l,3-benzothiazol-7-yl)carbamate. In a 25-mL round bottom flask, to a solution of tert-butyl N-(2-bromo-l,3-...

Claims

1. WSGR Docket No. 20012-705.601Claims1. A compound of Formula I:Formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:G is N or CR10; each R1is independently H, halogen, -CF3, -CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -NR2R3, -C(O)NR2R3, -NR2C(NH)NR2R3, - S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-Ci- C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or - CH(R4)NR2R3, wherein said Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R2is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, -(Ci-Ce alkyl)-(C6-Cio aryl), -(Ci-Cs heteroalkyl)-(C6- C10 aryl), -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl), -(Ci-Cs heteroalkyl)-(5- to 10- membered heteroaryl), -(Ci-Ce alkyl)-(3- to 10-membered heterocycloalkyl), -(Ci-Cs heteroalkyl)-(3- to 10-membered heterocycloalkyl), or 3- to 10-membered heterocycloalkyl, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R3is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), or -C(0)0-(C6-Cio aryl), wherein said Ci-C6alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10WSGR Docket No. 20012-705.601 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R10; orR2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl, wherein said 4- to 8-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Rlb; each R4is independently H, deuterium, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each Q is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -S-, -S(O)-, -S(O)2- -C(R5)=C(R5)-, — C=C— , an amino acid or a derivative thereof, Ce-Cio arylene, 5- to 10- membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R5is independently H, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or an albumin-binding moiety, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, wherein each said albuminbinding moiety is independently selected from the group consisting of:WSGR Docket No. 20012-705.601wherein * indicates a point of attachment; each R6is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(Ce-Cio aryl), -C(O)O-(Ci-Ce alkyl), -C(0)0-(Ce-Cio aryl), or said albuminbinding moiety described above, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;R10is independently H, D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ci-Ce heteroalkyl, -NR2R3, CN or NO2, wherein each C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4 alkyl)2 or CN, or R10is R1; each Rlais independently deuterium, halogen, -CN, -OH, -OCH3, C1-C4 haloalkyl, - OS(O)(C1-C4alkyl), -OS(0)(C6-Cio aryl),-(CH2)kC(O)OH, -(CH2)kC(O)O(Ci-C4alkyl), - (CH2)kC(O)(Ci-C4 alkyl), or -NR2R3, or two Rla, together with the atoms to which they are attached, form a 4- to 6-membered heterocylyl, wherein each C1-C4 alkyl, Ce-Cio aryl, or 4- to 6- membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4alkyl)2or CN; each Rlbis independently deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH, oxo, -C(O)NR2R3, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, or -NR2R3, where each said C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy is optionally substituted by 1 or 2 OH, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3;WSGR Docket No. 20012-705.601 each Rlcis independently deuterium, halogen, -CN, -C(O)OH, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) OCi- C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) C1-C4 alkyl, C1-C4 haloalkoxy, -OH, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4 alkyl)kNR2C(NH)NR2R3, or -NR2R3, where each said C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is optionally substituted by 1 or 2 -OH, halogen, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3; each k is independently 0, 1, 2, or 3; each m is independently an integer from 2 to 25; each n is independently 1, 2, or 3;Y is H, R1, or -LL-Z;LL is a bond or a divalent linker connecting Q and Z; andZ is (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye.

2. The compound of claim 1 , wherein Y is H.

3. The compound of claim 1, wherein Y is halogen.

4. The compound of claim 1, wherein Y is -LL-Z.

5. The compound of claim 4, wherein:LL is -E-(J)P-;E is a bond, carbon, nitrogen, or a 3- to 14-membered ring system;J is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -O-CH2-CH2-, -CH2-O- CH2-, -CH2-CH2-O-, -S-, -S(O)-, -S(O)2-, -C(R5)=C(R5)-, -C=C-, an ammo acid or derivative thereof, Ce-Cio arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; and p is an integer from 2 to 25.

6. A compound of Formula II:WSGR Docket No. 20012-705.601Formula II or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, wherein:G is N or CR10; each R1is independently H, halogen, -CF3, -CN, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, -NR2R3, -C(O)NR2R3, -NR2C(NH)NR2R3, - S(O)NR2R3, -S(O)2NR2R3, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-Ci- C4alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or - CH(R4)NR2R3, wherein said Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R2is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, -(Ci-Ce alkyl)-(C6-Cio aryl), -(Ci-Cs heteroalkyl)-(C6- C10 aryl), -(Ci-Ce alkyl)-(5- to 10-membered heteroaryl), -(Ci-Cs heteroalkyl)-(5- to 10- membered heteroaryl), -(Ci-Ce alkyl)-(3- to 10-membered heterocycloalkyl), -(Ci-Cs heteroalkyl)-(3- to 10-membered heterocycloalkyl), or 3- to 10-membered heterocycloalkyl, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R3is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(C6-Cio aryl), -C(O)O-(Ci-C6alkyl), or -C(0)0-(C6-Cio aryl), wherein said Ci-C6alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb,WSGR Docket No. 20012-705.601 wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R10; orR2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl, wherein said 4- to 8-membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 Rlb; each R4is independently H, deuterium, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each Q is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -S-, -S(O)-, -S(O)2- - C(R5)=C(R5)- , — C=C— , an amino acid or a derivative thereof, Ce-Cio arylene, 5- to 10- membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each R5is independently H, halogen, -CF3, -CN, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, or an albumin-binding moiety, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc, wherein each said albuminbinding moiety is independently selected from the group consisting of:WSGR Docket No. 20012-705.601wherein * indicates a point of attachment; each R6is independently H, Ci-Ce alkyl, Ci-Cs heteroalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, -C(O)-(Ci-Ce alkyl), -C(0)-(Ce-Cio aryl), -C(O)O-(Ci-Ce alkyl), -C(0)0-(Ce-Cio aryl), or said albuminbinding moiety described above, wherein said Ci-Ce alkyl or Ci-Cs heteroalkyl is optionally substituted by 1, 2, 3 or 4 Rla, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc;R10is independently H, D, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ci-Ce heteroalkyl, -NR2R3, CN or NO2, wherein each C1-C4 alkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4 alkyl)2 or CN, or R10is R1; each Rlais independently deuterium, halogen, -CN, -OH, -OCH3, C1-C4 haloalkyl, - OS(O)(C1-C4alkyl), -OS(0)(C6-Cio aryl),-(CH2)kC(O)OH, -(CH2)kC(O)O(Ci-C4alkyl), - (CH2)kC(O)(Ci-C4 alkyl), or -NR2R3, or two Rla, together with the atoms to which they are attached, form a 4- to 6-membered heterocylyl, wherein each C1-C4 alkyl, Ce-Cio aryl, or 4- to 6- membered heterocyclyl is optionally substituted by one or more halogen, OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, NH2, NH(Ci-C4 alkyl), N(CI-C4alkyl)2or CN; each Rlbis independently deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OH, oxo, -C(O)NR2R3, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4 alkyl, or -NR2R3, where each said C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy is optionally substituted by 1 or 2 OH, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3;WSGR Docket No. 20012-705.601 each Rlcis independently deuterium, halogen, -CN, -C(O)OH, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ce-Cio aryl, 5- to 10-membered heteroaryl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) OCi- C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O) C1-C4 alkyl, C1-C4 haloalkoxy, -OH, -(CH2)kC(O)OH, -(CH2)kC(O)OCi-C4alkyl, -(CH2)kC(O)Ci-C4alkyl, -(O-C1-C4 alkyl)k(O-Ci-C4 alkyl)n(O-Ci-C4 alkyl)kNR2C(NH)NR2R3, or -NR2R3, where each said C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Ce-Cio aryl, or 5- to 10-membered heteroaryl, is optionally substituted by 1 or 2 -OH, halogen, C1-C2 alkoxy, C1-C2 haloalkoxy, or -NR2R3;E is a bond, carbon, nitrogen, or a 3- to 14-membered ring system;J is independently a bond, -CR5R5-, -C(O)-, -NR6-, -O-, -O-CH2-CH2-, -CH2-O- CH2-, -CH2-CH2-O-, -S-, -S(O)-, -S(O)2-, -C(R5)=C(R5)-, -C=C-, an ammo acid or derivative thereof, Ce-Cio arylene, 5- to 10-membered heteroarylene, C3-C10 cycloalkylene, or 3- to 10-membered heterocyloalkylene, wherein said C3-C10 cycloalkyl or 3- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, wherein said Ce-Cio aryl or 5- to 10- membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc; each k is independently 0, 1, or 2; each m is independently an integer from 2 to 25; each n is independently 1, 2, or 3; p is an integer from 2 to 25; q is 2, 3, or 4; andZ is (i) a metal chelator, optionally bound to a radionuclide; (ii) a fluorophore; or (iii) a dye.

7. The compound of any one of claims 1-6, wherein R1is independently halogen, -CF3, - CN, Ci-C8alkyl, C2-C8alkenyl, Ci-C8alkoxy, -C(O)NR2R3, -NR2C(NH)NR2R3, -N(Ci-C8alkyl)R3, -N(CI-C8alkyl)(C(O)O(Ci-C6alkyl), -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kC(O)OH, -(O-C1-C4 alkyl)k(O-Ci-C4alkyl)n(O-Ci-C4alkyl)kNR2C(NH)NR2R3, -CH2(R4), -CH(R4)2, -C(R4)3, or -CH(R4)NR2R3, wherein said C1-C4 alkyl, Ci-C8alkyl, C2-C8alkenyl, or Ci-C8alkoxy is optionally substituted by 1, 2, 3 or 4 Rla.

8. The compound of claim 7, wherein G is CH.WSGR Docket No. 20012-705.6019. The compound of any one of claims 1-6, wherein R1is independently halogen, -CF3, - CN, thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, imidazole, phenyl, pyridine, pyrazine, pyridazine, pyrimidine, pyridazin-3(2H)-one, indole, naphthalene, benzo [d]isoxazole, benzo[d]oxazole, benzo [d] isothiazole, benzo[d]imidazole, benzo[d][l,3]dioxole, imidazo[l,5- a]pyridine, pyrazolo[l,5-a]pyridine, pyrrolo[2,3-b]pyridine, indazole, quinazoline, 1,5- naphthyridine, 1,8-naphthyridine,, wherein said thiophene, furan, pyrrole, thiazole, oxazole, pyrazole, imidazole, phenyl, pyridine, pyrazine, pyridazine, pyrimidine, pyridazin-3(2H)-one, indole, naphthalene, benzo[d]isoxazole, benzo[d] oxazole, benzo[d] isothiazole, benzo[d] imidazole, benzo[d][l,3]dioxole, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, pyrrolo[2,3-b]pyridine, indazole, quinazoline, 1,5 -naphthyridine, or 1,8- naphthyridine is optionally substituted by 1, 2, 3 or 4 Rlc.

10. The compound of claim 9, wherein G is CH.

11. The compound of any one of claims 1-6, wherein R1is independently halogen, -CF3, - CN, Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, 3,6- dihydro-2H-pyran, azetidine, pyrrolidine, piperidine, imidazolidine, piperazine, hexahydropyrimidine, hexahydropyridazine, oxazolidine, morpholine, 1,3-oxazinane, or 1, 2- oxazinane, wherein said C3-C8 cycloalkyl, Cs-Cs cycloalkenyl, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, 3,6-dihydro-2H-pyran, azetidine, pyrrolidine, piperidine, imidazolidine, piperazine, hexahydropyrimidine, hexahydropyridazine, oxazolidine, morpholine, 1,3-oxazinane, or 1, 2-oxazinane is optionally substituted by 1, 2, 3 or 4 Rlb.

12. The compound of claim 11, wherein G is CH.

13. The compound of any one of claims 6-12, wherein -E-(J)P- comprisesWSGR Docket No. 20012-705.601towards Q, wherein # indicates connection towards Z, wherein each of e and d is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8, and wherein f is independently 1, 2, 3, 4, 5, 6, 7 or 8, with the proviso that at least one of e and d within the same bracket is not 0.WSGR Docket No. 20012-705.601$ \ / # $ \N / # I14. The compound of any one of claims 6-12, wherein -E- comprises $ , $wherein $ indicates connection towards Q, wherein # indicates connection towards Z, whereinis Ce-Cio aryl, 5- to 10-membered heteroaryl, C3-C14 cycloalkyl, C5-C14 cycloalkenyl, or 3- to 14-membered heterocycloalkyl, wherein said C3-C14 cycloalkyl, C5-C14 cycloalkenyl, or 3- to 14-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 Rlb, and wherein said Ce-Cio aryl or 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3 or 4 Rlc.

15. The compound of any one of claims 1 or 4-14, wherein (i) Z is said metal chelator; and (ii) said metal chelator is: AAZTA, BAT, BAT-TM, Crown, Cyclen, CB-Cyclam, DO2A, CB- DO2A, DO3A, H3HP-DO3A, Oxo-DO3A, p-NH2- Bn-Oxo-DO3A, DOTA, DOTA-3py, DOTA- PA, DOTA-GA, DOTA-4AMP, DOTA-2py, DOTA-lpy, DOTAMAP, DOTAGA, DOTAGA- anhydnde, DOTMA, DOTASA, DOTAM, DOTP, p-SCN-Bn-DOTA, DOTPA, DOTMP,DOTPM, DTP A, CHX-A"-DTPA, p-NH2-Bn-CHX-A"-DTPA, p-SCN-DTPA, p-SCN-Bz-Mx- DTPA, 1B4M-DTPA, p-SCN-BnlB-DTPA, p-SCN-Bn-lB4M-DTPA, p-SCN-Bn-CHX-A"- DTPA, CHX-A"-EDTA, MeO-DOTA-NCS EDTA, HEHA, HEHA-NCS, p-SCN-Bn- HEHA, NOTA, NOTP, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM-TE2A, PEPA, p-SCN-Bn-PEPA, TETPA, t-Bu-calix[4]arene- tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, H2azapa, Hsdecapa, bispa2, PUpypa, PUoctapa, PUCHXoctapa, p-SCN-Bn-PUoctapa, p- SCN-Bn-H4octapa, TTHA, p-NO2-Bn- neunpa, PEoctox, H2macropa, H2bispa2, PEphospa, H6phospa, p-SCN-Bn-H6phospa, TETA, p- NO2-Bn-TETA, TRAP, TP A, HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMSA, DMPS, DHLA, lipoic acid, TGA, BAL, Bis- thioseminarabazones, p-SCN-NOTA, nNOTA, NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p- C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycuplAlB, pycup2A, THP,WSGR Docket No. 20012-705.601DEDPA, H2DEDPA, p-SCN-Bn-H2DEDPA, p-SCN-Bn- TCMC, motexafin, NTA, NOC, 3p-C- NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM,CP256, C-NE3TA, C-NE3TA-NCS, NODASA, NETA- monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO- BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, Lpy, or EuK-106, or a derivative thereof.

16. The compound of any one of claims 1 or 4-14, wherein (i) Z is said metal chelator; andWSGR Docket No. 20012-705.601salt thereof, wherein X indicates a point of attachment.

17. The compound of any one of claims 1 or 4-14, wherein (i) Z is said metal chelator; and (ii) said metal chelator is DOTA or a derivative thereof.

18. The compound of any one of claims 1 or 4-17, wherein said radionuclide is225Ac,209Bi, 213BI,134Ce,62Cu,64Cu,67Cu,223Fr,68Ga,148Gd,inIn,177Lu,212Pb,213Po,153Pm,223Ra,105Rh, 149Tb, 152Tb, 99mTc, 167Tm, 227^ 229^ 90^ 175^,Or89Zr.

19. The compound of any one of claims 1 or 4-17, wherein said radionuclide is72As,134Ce, 55Co,58gCo,61Cu,64Cu,66Ga,67Ga, '" in,132La,133La,177Lu,52Mn,43Sc,44Sc,153Sm,83Sr,152Tb, "mTc545T1, 86^Qr89Zf20. The compound of any one of claims 1 or 4-17, wherein said radionuclide is225Ac,211At, 199Au,212BI,213BI,67CU,166HO,177LU,212Pb,223Ra,186Re,188Re,105Rh,47Sc,153Sm,161Tb,149Tb, 227Th or90Y.

21. The compound of any one of claims 1 or 4-14, wherein Z is said fluor ophore.WSGR Docket No. 20012-705.60122. The compound of any one of claims 1 or 4-14, wherein Z is said dye.

23. The compound of any one of claims 1 or 4-14, wherein Z is modified pentamethine, heptamethine, ATTO 665, macrocycle, DyLight derivative, Alexa Fluor derivative, BODIPY, metallic quantum dot, CdTe-QDs, ZW800-1, IR800, IR820, ICG, 800CW, metallic nanocluster, silver nanocluster, HypoxyFluor, dicyanomethylene-4H-pyran, or Merocyanine.

24. A compound of any one of claims 1-23, wherein the compound comprises a structure in Table 1 to Table 17, or a derivative thereof.

25. A compound, wherein the compound is:pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof.

26. A compound, wherein the compound is:pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof.

27. A compound, wherein the compound is:pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof.

28. A compound, wherein the compound is:WSGR Docket No. 20012-705.601pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof.

29. A compound, wherein the compound is:pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof.

30. A pharmaceutical composition comprising a compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

31. The pharmaceutical composition of claim 30, further comprising one or more stabilizing agent.

32. A method of treating a disease or disorder in a subject, the method comprising:(b) administering to said subject an effective amount of a compound of any one of claims 1-29 or a pharmaceutical composition of claims 30 or 31.

33. The method of claim 32, wherein said disease or disorder is cancer, and wherein said cancer is selected from the group consisting of clear-cell renal cell carcinoma, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head & neck cancer, oral cancer, and kidney cancer.

34. The method of claim 33, wherein said cancer is clear-cell renal cell carcinoma.

35. The method of claim 32, wherein said disease or disorder is inflammation.

36. The method of claim 32, wherein said disease or disorder is associated with carbonic anhydrase IX (CA9) over expression in a tissue of said subject.

37. The method of any one of claims 32-36, wherein the compound is any one of claim 20 or claims 24-29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.WSGR Docket No. 20012-705.60138. A method of optical imaging or diagnostic imaging of a biological tissue that expresses carbonic anhydrase IX (CA9), the method comprising:(c) contacting said biological tissue of a subject with a compound of any one of claims 1- 29 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claims 30 or 31; and(d) detecting an optical signal indicative of cells that overexpress CA9 in said biological tissue.

39. The method of claim 38, wherein the compound is any one of claim 19 or claims 24-29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.

40. A method of imaging a tumor tissue that expresses carbonic anhydrase IX (CA9), the method comprising:(c) contacting said tumor tissue of a subject with a compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claims 30 or 31; and(d) detecting an optical signal indicative of cells that overexpress CA9 in said tumor tissue.

41. The method of claim 40, wherein the compound is any one of claim 19 or claims 24-29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (i) the compound or the pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient.

42. The method of any one of claims 38-41, further comprising: measuring a concentration of said compound accumulated in said subject.

43. The method of any one of claims 38-42, further comprising: measuring an amount of radiation emitted from said radionuclide, where said compound comprises said radionuclide, said fluorophore, or said dye.

44. The method of any one of claims 38-43, wherein said detecting is conducted by positron emission tomography (PET), single photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI).WSGR Docket No. 20012-705.60145. The method of claim 43 or claim 44, further comprising: performing an imaging scan, detecting a measurable signal due to said radionuclide or said fluorophore or said dye from the subject; and generating an image from said measurable signal, thereby obtaining an image of a tissue or an organ of said subject.

46. A method of preparing a compound of any one of claims 1-23, wherein Z is a metal chelator bound to a radionuclide, the method comprising a step of reacting a compound of any one of claims 1-29, wherein Z is a metal chelator with a radionuclide in the presence of a pH buffer.

47. The method of claim 46, wherein the step is carried out in a pH of about 5.2 to about 5.5.

48. The method of 46 or 47, wherein the pH buffer comprises sodium acetate.

49. The method of any one of claims 46-48, wherein the step is carried out at a temperature of about 70 °C.

50. The method of any one of claims 46-49, wherein the step is carried out for about 30 min.

51. A compound of F ormula III,Formula III or a pharmaceutically acceptable salt solvate, prodrug, stereoisomer or tautomer thereof, wherein R1is selected from the group consisting of -H, halo, -CF3, -CN, Ci-Cs alkyl, Ci-Cs alkenyl, Ci-C8alkoxy, -NR2R3, -NR2C(=O)R2, -NR2C(=O)OR2, -NR2C(NH)NR2R3, -O-C1-C4 alkyl,cycloalkyl, 3- to 10- membered heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl, wherein each of C3- C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3, or 4 Rla, Rlb, or Rlc; each of Rla, Rlb, and Rlcis independently selected from the group consisting of -H, halo, CN-, carboxyl, alkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, and phenyl; each of R2, R3, and R4is independently selected from the group consisting of -H, Ci-Cs alkyl, and Ci-Cs alkyl-O-C(O)-;WSGR Docket No. 20012-705.601Q is -O-Ci-Cio alkylene-, or C1-C10 alkylene; m is 1, 2, 3, 4, 5, or 6;E is selected from the group consisting ofeach of R11, R12, and R13is independently selected from the group consisting of -H, C1-C4 alkyl, aminoCi-C4 alkyl, -C1-C4 alkylene-S-Ci-C4 alkyl, alkylthioalkyl, phenyl, benzyl, imidazolyl, alkylimidazole andJ is selected from the group consisting of a bond, -O-, -C(=O)-, -CH2-, -NH-, -NHC(O)-, -NHC(O)-CI-C4alkylene-, -Ci-C8alkylene-NH-, -(CH2)2-O-(CH2)2-NH-, and -(CH2)3-O-(CH2)2- NH-; and p is an integer from 1 to 25.Z is selected from the group consisting of DOTA, DOTA-lPy, DOTA-2Py, DOTA-3Py, DOTA-GA, D0TA-4AMP, PA-DOTA, DOTAMAP, DOTAGA-anhydnde, DOTMA, DOTASA, DOTAM, DOTP, DOTMP, DOTPA, p-SCVN-Bn-DOTA, MeO-DOTA-NCS, HEHA, HEHA-NCS, NOTA, NOD AGA, NOTP, NOTMP, TE2A, CB-TE2A, TE2P, CB-TE2P, CB-TE1A1P- MM-TE2A, DM-TE2A, TETA, TETPA, p-NO2-Bn-TETA, p-NH2-Bn-TE3A, PEPA, p-SCN-Bn-PEPA, HBED, SHBED, HBED-CC, and (HBED-CC)TFP.

52. The compound of claim 51, wherein Z is HBED, NOTA, or DOTA.

53. The compound of claim 51 or 52, wherein the linkerof Formula III is selected from the group consisting of:WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.60154. The compound of claim 51 or 52, wherein the linkerWSGR Docket No. 20012-705.60155. The compound of any one of claims 51 to 54, wherein R1is halo, carboxyl, cyclooctylamino, pyridinyl, thiophenyl, thiazolyl, furanyl, imidazolyl, cyclopropyl, cyclobutyl, indazolyl, indolizinyl, pyrolyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl,57. The compound of any one of claims 51 to 56, wherein Z is HBED, NOTA, or DOTA;WSGR Docket No. 20012-705.60158. The compound of claim 51, which is selected from group consisting of:WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.601WSGR Docket No. 20012-705.60159. The compound of any one of claims 51 to 58, which is bound to a radionuclide which is selected from the group consisting of225Ac,209BI,213BI,134Ce,62Cu,64Cu,67Cu,223Fr,68Ga,148Gd,inIn,177LU,212Pb,213Po,153Pm,223Ra,105Rh,149Tb,152Tb, "mTc,167Tm,227Th,229Th,90Y,175Yb, and89Zr.

60. The compound of any one of claims 51 to 58, wherein the radionuclide is177Lu,90Y,225Ac,68Ga, or64Cu.

61. A compound of F ormula IV,ormula IV or a pharmaceutically acceptable salt solvate, prodrug, stereoisomer or tautomer thereof, wherein R1is selected from the group consisting of -H, halo, -CF3, -CN, Ci-Cs alkyl, Ci-Cs alkenyl, Ci-C8alkoxy, -NR2R3, -NR2C(=O)R2, -NR2C(=O)OR2, -NR2C(NH)NR2R3, -O-C1-C4 alkyl,cycloalkyl, 3- to 10-WSGR Docket No. 20012-705.601 membered heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl, wherein each of C3- C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Ce-Cio aryl and 5- to 10-membered heteroaryl is optionally substituted by 1, 2, 3, or 4 Rla, Rlb, or Rlc; each of Rla, Rlb, and Rlcis independently selected from the group consisting of -H, halo, CN-, carboxyl, alkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, and phenyl; each of R2, R3, and R4is independently selected from the group consisting of -H, Ci-Cs alkyl, and Ci-Cs alkyl-O-C(O)-;Q is -O-Ci-Cs alkylene-, or Ci-Cs alkylene; m is 1, 2, 3, 4, 5, or 6;E is selected from the group consisting ofeach of R11, R12, and R13is independently selected from the group consisting of -H, C1-C4 alkyl, aminoCi-C4 alkyl, -C1-C4 alkylene-S-Ci-C4 alkyl, alkylthioalkyl, phenyl, imidazolyl, andJ is selected from the group consisting of a bond, -O-, -C(=O)-, -CH2-, -NH-, -NHC(O)-, -Ci-C8alkylene-NH-, -(CH2)2-O-(CH2)2-NH-, and -(CH2)3-O-(CH2)2-NH-; and p is an integer from 1 to 25.Z is selected from the group consisting of DOTA, DOTA-lPy, DOTA-2Py, DOTA-3Py, DOTA-GA, DOTA-4AMP, PA-DOTA, DOTAMAP, DOTAGA-anhydnde, DOTMA, DOTASA, DOTAM, DOTP, DOTMP, DOTPA, p-SCVN-Bn-DOTA, MeO-DOTA-NCS, HEHA, HEHA-NCS, NOTA, NOTP, NOTMP, TE2A, CB-TE2A, TE2P, CB-TE2P, CB- TE1A1P- MM-TE2A, DM-TE2A, TETA, TETPA, p-NO2-Bn-TETA, p-NH2-Bn-TE3A, PEPA, p-SCN-Bn-PEPA, HBED, SHBED, HBED-CC, and (HBED-CC)TFP.

62. The compound of claim 61, which is selected from group consisting of:WSGR Docket No. 20012-705.60163. The compound of claim 61 or 62, which is bound to a radionuclide which is selected from the group consisting of225Ac,209Bi,213Bi,134Ce,62Cu,64Cu,67Cu,223Fr,68Ga,148Gd,mIn,177LU,212Pb,213Po,153Pm,223Ra,105Rh,149Tb,152Tb, "mTc,167Tm,227Th,229Th,90Y,175Yb, and89Zr.

64. The compound of claim 61 or 62, wherein the radionuclide is177Lu,90Y,225Ac,68Ga, or64Cu.

65. A compound having the chemical structure:WSGR Docket No. 20012-705.601or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof.

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