TW202416974A - Extracellular hsp90 (ehsp90)-targeted radiopharmaceuticals and use thereof - Google Patents

Abstract

Compounds comprising a targeting moiety that specifically binds to HSP90, in particular, extracellular HSP90. Also disclosed are pharmaceutical compositions and methods of treating cancer with the same.

Description

Radiopharmaceuticals targeting extracellular HSP90 (eHSP90) and their uses

Heat shock protein 90 (HSP90) is a molecular chaperone that regulates protein folding to ensure correct conformation and translocation and to prevent protein aggregation. Many oncogenic proteins are HSP90 client proteins, such as epidermal growth factor receptor (EGFR) mutants, CDK4, hypoxia-induced factor (HIF)-1α, and matrix metallopeptidase 2 (MMP2).

A portion of HSP90, extracellular HSP90 (eHSP90), is identified on the surface of many cell types and may be a tumor antigen useful for eliciting a host immune response. Studies have shown that eHSP90 plays a key role in maintaining oncogenic protein homeostasis and is involved in the invasion and metastasis of various cancers, including breast cancer, making eHSP90 an attractive target for the development of cancer therapeutics.

HSP90 inhibition has been shown to have significant direct effects on cell cycle and DNA repair mechanisms, thus offering great promise in the treatment of a wide range of solid and hematologic malignancies. However, early clinical trials have demonstrated that some HSP90 inhibitors show limited efficacy and various side effects.

Therefore, there is a need to improve the treatment of cancer by targeting certain proteins (eg, eHSP90) with good efficacy and an acceptable safety profile.

The present invention includes the following insights: Certain radiopharmaceuticals that include a targeting moiety that specifically binds to HSP90, in particular eHSP90, can be effective as HSP90 radioligand therapy (RLT) for the treatment of cancer. Radioactive decay can cause direct physical damage (such as single-strand or double-strand DNA breaks) or indirect damage (such as bystander or crossfire effects) to biological molecules that make up cells. Drugs that deliver radionuclides to cancer cells (i.e., radiopharmaceuticals) provide a mechanism for producing DNA damage that has anti-cancer therapeutic effects. The present invention provides certain radiopharmaceuticals, specifically, small molecule-based radiopharmaceuticals that target HSP90 overexpressing tumors and use tantalum-225 ( ²²⁵ Ac), tantalum-177 ( ¹⁷⁷ Lu) or other suitable therapeutic radionuclides to target cancer cells to treat or ameliorate cancer (such as lung cancer, sarcoma, pancreatic cancer, breast cancer or colon cancer).

In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof: (I), wherein X is absent, C=O or (C=O)NR ¹ , R ¹ is H, alkyl, aryl, (C-CF ₃ )R ² or (SO ₂ )R ² , R ² is alkyl or aryl; Y is independently O or NR ³ , R ³ is H, alkyl, aryl or acyl; n is an integer from 0 to 5 (inclusive); Z ¹ and Z ² are independently absent, an amino acid unit, (C=O)NR ⁴ (CH ₂ CH ₂ )O or (C=O)NR ⁴ (CH ₂ CH ₂ )NR ⁵ , wherein each of R ⁴ and R ⁵ is independently H or alkyl or (C-CF ₃ )R ⁶ or (SO ₂ )R ⁶ , R ^Z1 and ^Z2 are alkyl or aryl groups; and W is a chelating agent selected from the group consisting of DOTA, DOTAGA, NOTA and NODAGA, each as defined in the embodiment section below, wherein when W is DOTA, at least one of ^Z1 and Z2 is an amino acid unit, or each of ^Z1 and ^Z2 is absent and n is equal to or less than 4; wherein the compound binds to HSP90; and wherein the compound further comprises a radionuclide chelated by the chelating agent as needed.

In some embodiments, the compounds of the present invention specifically bind to extracellular HSP90 (eHSP90).

In some embodiments, the compounds of the present invention have a structure of Formula II: (II), wherein each of X, Y, n, ^Z1 and ^Z2 is as defined above.

In some embodiments, the compound of Formula I or Formula II is characterized in that at least one of Z ¹ and Z ² is an amino acid unit.

In some embodiments, the compound of Formula I or Formula II is characterized in that the amino acid unit is formed by glycine (Gly), aspartic acid (Asp), glutamine (Glu), 2,4-diaminobutyric acid (Dab), 2,3-diaminopropionic acid (Dap), lysine (Lys) or arginine (Arg).

In some embodiments, the compound of Formula I or Formula II is characterized in that the amino acid unit is formed by glycine (Gly), aspartic acid (Asp), glutamine (Glu), 2,4-diaminobutyric acid (Dab), 2,3-diaminopropionic acid (Dap), lysine (Lys), arginine (Arg), or a combination thereof.

In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit comprises an organic moiety formed from Asp.

In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit is formed by Gly.

In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit is formed by Glu.

In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent.

In some embodiments, the compound of formula I or formula II is characterized in that X is C═O.

In some embodiments, the compound of Formula I or Formula II is characterized in that X is (C=O)NR ¹ , wherein R ¹ is H, alkyl or aryl.

In some embodiments, the compound of Formula I or Formula II is characterized in that X is (C=O)NH.

In some embodiments, the compound of formula I or formula II is characterized in that n is 0.

In some embodiments, the compound of Formula I or Formula II is characterized in that n is 1, 2 or 3.

In some embodiments, the compound of Formula I or Formula II is characterized in that n is 4 or 5.

In some embodiments, the compound of Formula I or Formula II is characterized in that n is 4.

In some embodiments, the compound of formula I or formula II is characterized in that n is 5.

In some embodiments, the compound of formula I or formula II is characterized in that each Y is independently O, NH or N(C _1-6 alkyl). In some embodiments, the compound of formula I or formula II is characterized in that each Y is independently O. In some embodiments, the compound of formula I or formula II is characterized in that each Y is independently NH.

In some embodiments, the compound of Formula I or Formula II is characterized in that each of Z ¹ and Z ² is absent.

In some embodiments, the compound of formula I or formula II is characterized in that Z ¹ is absent.

In some embodiments, the compound of Formula I or Formula II is characterized in that Z ² is absent.

In some embodiments, the compound of formula I or formula II is characterized in that Z ¹ is an amino acid unit.

In some embodiments, the compound of formula I or formula II is characterized in that Z ² is an amino acid unit.

In some embodiments, the compound of formula I or formula II is characterized in that Z ¹ is (C=O)NH(CH ₂ CH ₂ )NH. In some embodiments, the compound of formula I or formula II is characterized in that Z ² is (C=O)NH(CH ₂ CH ₂ )NH.

In some embodiments, the compound of formula I or formula II is characterized in that Z ¹ is (C=O)NH(CH ₂ CH ₂ )N(C _1-6 alkyl). In some embodiments, the compound of formula I or formula II is characterized in that Z ² is (C=O)NH(CH ₂ CH ₂ )N(C _1-6 alkyl).

In some embodiments, the compound of formula I or formula II is characterized in that Z ¹ is (C=O)N(C _1-6 alkyl)(CH ₂ CH ₂ )NH. In some embodiments, the compound of formula I or formula II is characterized in that Z ² is (C=O)N(C _1-6 alkyl)(CH ₂ CH ₂ )NH.

In some embodiments, the compound of formula I or formula II is characterized in that Z ¹ is (C=O)N(C _1-6 alkyl)(CH ₂ CH ₂ )N(C _1-6 alkyl). In some embodiments, the compound of formula I or formula II is characterized in that Z ² is (C=O)N(C _1-6 alkyl)(CH ₂ CH ₂ )N(C _1-6 alkyl).

In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent, n is 0, Z ¹ is absent, and Z ² is an amino acid unit.

In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z ¹ is an amino acid unit, and Z ² is absent.

In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z ¹ is absent, and Z ² is an amino acid unit.

In some embodiments, the amino acid unit is selected from the group consisting of: , , , , , , and .

In some embodiments, the compound of Formula I or Formula II is characterized in that X is (C=O)NH, n is 4 or 5, and each of ^Z1 and ^Z2 is absent.

In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z ¹ is absent, and Z ² is (C=O)NH(CH ₂ CH ₂ )NH.

In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent, n is 0, and each of ^Z1 and ^Z2 is absent.

In some embodiments, the compound of Formula I or Formula II is selected from the group consisting of: , , , , , , , , , , , and .

In some embodiments, the compound of formula I or formula II is characterized in that each compound comprises a radionuclide selected from the group consisting of: ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ⁵⁵ Co, ⁶⁰ Cu, ⁶¹ Cu, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁸² Rb, ⁸⁶ Y, ⁸⁷ Y, ⁸⁹ Zr, ⁹⁰ Y, ⁹⁷ Ru, ⁹⁹ Tc, ^99m Tc, ¹⁰⁵ Rh, ¹⁰⁹ Pd, ¹¹¹ In, ^117m Sn, ¹³³ La, ¹³⁴ Ce, ¹⁴⁹ Pm, ¹⁴⁹ Tb, ¹⁵³ Sm, ¹⁵² Tb, ¹⁵⁵ Tb, ¹⁶¹ Tb, ¹⁶⁶ Ho, ¹⁷⁷ Lu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁹⁸ Au, ¹⁹⁹ Au, ²⁰¹ Tl, ²⁰³ Pb, ²¹¹ At, ²¹² Pb, ²¹² Bi, ²¹³ Bi, ²²³ Ra, ²²⁵ Ac, ²²⁷ Th and ²²⁹ Th.

In certain embodiments, the radionuclide is selected from the group consisting of ⁶⁸ Ga, ⁸⁹ Zr, ⁹⁰ Y, ¹¹¹ In, ¹⁷⁷ Lu, and ²²⁵ Ac.

In certain embodiments, the radionuclide is ¹⁷⁷ Lu or ²²⁵ Ac.

In certain embodiments, the radionuclide is ¹⁷⁷ Lu.

In certain embodiments, the radionuclide is ²²⁵ Ac.

In another aspect, the present invention also encompasses a pharmaceutical composition comprising one of the compounds described above and a pharmaceutically acceptable excipient.

Still within the scope of the present invention is a method of treating cancer comprising administering to a subject in need thereof one of the compounds described above or the pharmaceutical composition described above.

In some embodiments, a method of treating cancer comprises administering to a subject in need thereof a first dose of one of the compounds or compositions described above in an amount effective for a radiation therapy program, followed by administering a subsequent dose of one of the compounds or compositions described above in a therapeutically effective amount.

In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.

Related applications

This application claims priority to U.S. Provisional Application No. 63/401,227 filed on August 26, 2022, the entire contents of which are incorporated herein by reference for all purposes.

The present invention relates to radiopharmaceutical compounds comprising a targeting moiety that specifically binds to HSP90, in particular extracellular HSP90 (eHSP90).

Radiolabeled targeting molecules (also called radiopharmaceuticals) are designed to target proteins or receptors (e.g., eHSP90) that are upregulated and/or diseased cells (e.g., tumor cells) in disease states to deliver a radioactive payload to damage and kill the cells of interest. The radiopharmaceuticals provided in the present invention that target eHSP90 can be used to treat various cancers, including (but not limited to) small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, breast cancer, and colon cancer. Definitions Chemical Terms

Unless otherwise specified, as used herein, the term "alkyl" includes both straight and branched chain saturated groups of 1 to 20 carbons (eg, 1 to 10 or 1 to 6). Alkyl is exemplified by methyl, ethyl, n- and i-propyl, n-, sec-, i- and t-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or (in the case of an alkyl group of two carbons or more) four substituents independently selected from the group consisting of: (1) C _1-6 alkoxy; (2) C _1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., —NH ₂ ) or substituted amino (i.e., —N( ^RN1 ) ₂ , wherein R ^N1 is as defined for amino); (4) C _6-10 aryl-C _1-6 alkoxy; (5) azido; (6) halogen; (7) (C 6-10 aryl) _(2-9 heterocyclic)oxy; (8) hydroxyl, optionally substituted with an O protecting group; (9) nitro; (10) pendoxy (e.g., carboxyaldehyde or acyl); (11) C _1-7 spirocyclic group; (12) thioalkoxy; (13) thiol; (14) -CO ₂ RA ^' , optionally substituted with an O protecting group and wherein ^RA' is selected from the group consisting of: (a) C _1-20 alkyl (e.g., C _1-6 alkyl), (b) C _2-20 alkenyl (e.g., C _2-6 alkenyl), (c) C _6-10 aryl, (d) hydrogen, (e) C _1-6 alkane-C _6-10 aryl, (f) amino-C _1-20 alkyl, (g) -(CH ₂ ) _s2 (OCH ₂ CH ₂ ) _s1 (CH ₂ ) _s3 OR' wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C _1-20 alkyl, and (h) -NR ^N1 (CH ₂ ) _s2 (CH ₂ CH ₂ O) _s1 (CH ₂ ) _s3 NR ^N1 amino-polyethylene glycol wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each R ^N1 is independently hydrogen or optionally substituted C _1-6 alkyl; (15) -C(O)NR ^B' R ^C' , wherein each of RB ^' and RC ^' is independently selected from the group consisting of (a) hydrogen, (b) _C1-6 alkyl, (c) _C6-10 aryl, and (d) _C1-6 alkane- _C6-10 aryl; (16) _-SO2RD ^' , wherein ^RD' is selected from the group consisting of (a) _C1-6 alkyl, (b) _C6-10 aryl, (c) _C1-6 alkane- _C6-10 ^aryl , and (d) hydroxyl; (17) _-SO2NRRE'RF ^' , wherein each of RE ^' and ^RF' is independently selected from the group consisting of (a) hydrogen, (b) _C1-6 alkyl, (c) _C6-10 aryl, and (d) _C1-6 alkane- _C6-10 aryl; (18) -C(O) ^RG' , wherein ^RG' is selected from the group consisting of: (a) _C1-20 alkyl (e.g., _C1-6 alkyl), (b) _C2-20 alkenyl (e.g., _C2-6 alkenyl), (c) _C6-10 aryl, (d) hydrogen, (e) _C1-6 alkane- _C6-10 aryl, (f) amino- _C1-20 alkyl, (g) polyethylene _{glycol of -(CH2)s2(OCH2CH2)s1(CH2)s3OR ' , wherein s1 is an} integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or _C1-20 alkyl, and (h) ^-NRN1 (CH ₂ ) _s2 (CH ₂ CH ₂ O) _s1 (CH ₂ ) _s3 NR ^N1 amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each ^RN1 is independently hydrogen or an optionally substituted C _1-6 alkyl group; (19) -NR ^H'C (O) ^RI' , wherein RH ^' is selected from the group consisting of (a1) hydrogen and (b1) C _1-6 alkyl, and RI ^' is selected from the group consisting of (a2) C _1-20 alkyl (e.g., C _1-6 alkyl), (b2) C _2-20 alkenyl (e.g., C _2-6 alkenyl), (c2) C (d2) hydrogen, (e2) C _1-6 alkane- _{C 6-10 aryl} , (f2) amino-C _1-20 alkyl, (g2) -(CH ₂ ) _s2 (OCH ₂ CH ₂ ) _s1 (CH ₂ ) _s3 OR' polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C _1-20 alkyl, and (h2) -NR ^N1 (CH ₂ ) _s2 (CH ₂ CH ₂ O) _s1 (CH ₂ ) _s3 NR ^N1 amino-polyethylene glycol, wherein s1 is 1 to 10 wherein each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each R ^N1 is independently hydrogen or an optionally substituted C _1-6 alkyl group; (20) -NR ^J' C(O)OR ^K' , wherein R ^J' is selected from the group consisting of (a1) hydrogen and (b1) C _1-6 alkyl, and R ^K' is selected from the group consisting of (a2) C _1-20 alkyl (e.g., C _1-6 alkyl), (b2) C _2-20 alkenyl (e.g., C _2-6 alkenyl), (c2) C _6-10 aryl, (d2) hydrogen, (e2) C _1-6 alkane-C _6-10 aryl, (f2) amino-C _1-20 alkyl, (g2) -(CH ₂ ) _s2 (OCH ₂ CH ₂ ) _s1 (CH ₂ ) _s3 OR', wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C _1-20 alkyl, and (h2) -NR ^N1 (CH ₂ ) _s2 (CH ₂ CH ₂ O) _s1 (CH ₂ ) _s3 NR ^N1 amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each R ^N1 is independently hydrogen or optionally substituted C _1-6 alkyl; and (21) amidine. In some embodiments, each of these groups may be further substituted as described herein. For example, the alkylene of the C ₁ -alkaryl group may be further substituted with pendant oxy groups to provide the respective aryl substituents.

As used herein, the terms "alkylene", "alkylene" and the prefix "alk-" refer to saturated divalent hydrocarbon groups derived from straight or branched chain saturated hydrocarbons by removing two hydrogen atoms, and are exemplified by methylene, ethylene, isopropylene, and the like. The terms " _Cxy alkyl", " _Cxy alkylene", " _Cxy alkylene" and the prefix " _Cxy alk-" refer to alkyl or alkylene groups having between x and y carbons. Exemplary x values are 1, 2, 3, 4, 5, and 6, and exemplary y values are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C _1-6 , C _1-10 , C _2-5 , C _2-8 , C _2-10 , or C _2-20 alkyl or alkylene). In some embodiments, the alkylene group may be further substituted with 1, 2, 3, or 4 substituents as defined herein for an alkyl group.

Unless otherwise specified, as used herein, the term "alkenyl" refers to a monovalent straight or branched chain radical of 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl includes both cis and trans isomers. Alkenyl may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from amino, aryl, cycloalkyl, or heterocyclic (e.g., heteroaryl) as defined herein, or any of the exemplary alkyl substituents described herein.

As used herein, the term "alkynyl" refers to a monovalent straight or branched chain of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like. Alkynyl groups may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from aryl, cycloalkyl, or heterocycloalkyl (e.g., heteroaryl) as defined herein, or any of the exemplary alkyl substituents described herein.

As used herein, the term "amino" refers to -N( ^RN1 ) ₂ , wherein each ^RN1 is independently H, OH, _NO2 , N( ^RN2 ) ₂ , _{SO2ORN2 ,} ^{SO2RN2 , SORN2} , N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkylcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl or any described herein), heterocyclic (e.g., heteroaryl) or alkheterocyclic (e.g., alkheteroaryl), wherein each of these listed R ^N1 groups may be optionally substituted as defined herein for each group; or two R ^N1s are combined to form a heterocyclic or N-protecting group, and wherein each R ^N2 is independently H, alkyl or aryl. The amino group can be an unsubstituted amino group (i.e., _-NH2 ) or a substituted amino group (i.e. ^, -N( ^RN1 ) ₂ ). In a preferred embodiment, the amino group is _-NH2 or ^-NHRN1 , wherein ^RN1 is independently OH, _NO2 , _NH2 , NR ^N22 , _SO2OR ^N2 , _SO2RN2 , _SOR ^N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., tert-butoxycarbonylalkyl) or aryl, and each ^RN2 can be H, _C1-20 alkyl (e.g., _C1-6 alkyl) or _C6-10 aryl.

As used herein, the term "amino acid" refers to a molecule having a side chain, an amine group, and an acid group (e.g., a carboxyl group of -CO ₂ H or a sulfonyl group of -SO ₃ H), wherein the amino acid is linked to a parent molecular group by the side chain, the amine group, or the acid group (e.g., the side chain). In some embodiments, the amino acid is linked to the parent molecular group by a carbonyl group, wherein the side chain or the amine group is linked to the carbonyl group. Exemplary side chains include optionally substituted alkyl, aryl, heterocyclic, alkaryl, alkaryl heterocyclic, aminoalkyl, carbamoylalkyl, and carboxyalkyl groups. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamine, glycine, histidine, hydroxyvaleric acid, isoleucine, leucine, lysine, methionine, valeric acid, ornithine, phenylalanine, proline, pyrrole lysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine. The amino acid group may be optionally substituted with one, two, three or (in the case of two or more carbon amino acids) four substituents independently selected from the group consisting of: (1) C _1-6 alkoxy; (2) C 1-6 alkylsulfinyl; (3) amine, as defined herein (e.g., unsubstituted amine (i.e., -NH ₂ ) or substituted amine (i.e., -N( ^RN1 ) ₂ , wherein RN1 is as defined for an amine); (4) C 6-10 aryl-C _1-6 alkoxy; (5) azido; (6) halogen; (7) (C 2-9 ^heterocyclic )oxy; (8) hydroxy; (9) nitro; (10) pendoxy (e.g., carboxyaldehyde or acyl); (11) C _6-10 aryl-C _1-6 alkoxy; (12) C 6-10 aryl-C 1-6 alkoxy; (13) C 6-10 aryl-C 1-6 alkoxy; (14) C 6-10 aryl-C 1-6 alkoxy; (15) azido; (16) halogen; (17) (C _2-9 heterocyclic)oxy; (18) hydroxy; (19) nitro; (20) pendoxy (e.g., carboxyaldehyde or acyl); (21) C 6-10 aryl-C 1-6 alkoxy; (22) C 6-10 aryl-C 1-6 alkoxy; (23) C 6-10 aryl-C 1-6 alkoxy; (24) C 6-10 aryl-C 1-6 alkoxy; (25) C 6-10 aryl-C 1-6 alkoxy; (26) C 6-10 aryl-C 1-6 alk (12) thioalkoxy; (13) thiol; (14) -CO ₂ ^RA' , wherein ^RA' is selected from the group consisting of (a) C _1-20 alkyl (e.g., C _1-6 alkyl), (b) C _2-20 alkenyl (e.g., C _2-6 alkenyl), (c) C _6-10 aryl, (d) hydrogen, (e) C _1-6 alkane- _{C 6-10} aryl, (f) amino-C _1-20 alkyl, (g) -(CH ₂ ) _s2 (OCH ₂ CH ₂ ) _s1 (CH ₂ ) _s3 OR', wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), and each of s2 and s3 is independently 0 to 10. (h) -NR ^N1 (CH ₂ ) _s2 (CH ₂ CH ₂ O) _s1 (CH 2 ) _s3 NR ^N1 amino _- polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to ₄ ), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each ^RN1 is independently hydrogen or an optionally substituted C _1-6 alkyl group; (15) -C(O)NR ^{B' RC'} , wherein each of RB ^' and RC ^' is independently selected from the group consisting of: (a) hydrogen, (b) C _1-6 alkyl, (c) C (16) -SO ₂ ^{RD '} , wherein ^{RD '} is selected from the group consisting of ₍ a) C _1-6 alkyl, (b) C _6-10 aryl, (c) C _1-6 alk- _{C 6-10 aryl} , and (d) hydroxyl; (17) -SO ₂ NR ^{E ' RF '} , wherein each of RE ^' and RF ^' is independently selected from the group consisting of (a) hydrogen, (b) C _1-6 alkyl, (c) C _6-10 aryl, and (d) C _1-6 alk-C _6-10 aryl; (18) -C(O) ^{RG '} , wherein ^{RG '} _is selected from the group consisting of (a) C _1-20 alkyl (e.g., C _1-6 alkyl), (b) C 1-6 (c) C _6-10 aryl, _{(d) hydrogen, (e) C 1-6 alkane-C 6-10 aryl, (f) amino-C 1-20 alkyl , (} g) polyethylene glycol of -(CH ₂ ) _s2 (OCH _{2 CH 2} ) _s1 (CH ₂ ) _s3 OR', wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C _1-20 alkyl, and (h) -NR ^N1 (CH ₂ ) _s2 (CH ₂ CH ₂ O) _s1 (CH ₂ ) _s3 NR ^N1 amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each R ^N1 is independently hydrogen or an optionally substituted C _1-6 alkyl group; (19) -NR ^H'C (O) ^RI' , wherein ^RH' is selected from the group consisting of (a1) hydrogen and (b1) C _1-6 alkyl, and RI ^' is selected from the group consisting of (a2) C _1-20 alkyl (e.g., C _1-6 alkyl), (b2) C _2-20 alkenyl (e.g., C _2-6 alkenyl), (c2) C _6-10 aryl, (d2) hydrogen, (e2) C _1-6 alkane-C (f2) amino-C _1-20 alkyl, (g2) -(CH ₂ ) _s2 (OCH ₂ CH ₂ ) _s1 (CH ₂ ) _s3 OR', wherein s1 is an integer from 1 to 10 (e.g., 1 to ₆ or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and R' is H or C _1-20 alkyl, and (h2) -NR ^N1 (CH ₂ ) _s2 (CH ₂ CH ₂ O) _s1 (CH ₂ ) _s3 NR ^N1 amino-polyethylene glycol, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 wherein the alkylene group is an integer (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each ^RN1 is independently hydrogen or an optionally substituted _C1-6 alkyl group; (20) -NR ^J'C (O)OR ^K' , wherein R ^J' is selected from the group consisting of (a1) hydrogen and (b1) _C1-6 alkyl, and R ^K' is selected from the group consisting of (a2) _C1-20 alkyl (e.g., _C1-6 alkyl), (b2) _C2-20 alkenyl (e.g., _C2-6 alkenyl), (c2) _C6-10 aryl, (d2) hydrogen, (e2) _C1-6 alkane- _C6-10 aryl, (f2) amino- _C1-20 alkyl, (g2) -( _CH2 ) _s2 ( _{OCH2CH2 ) s1} ( _CH2 ) _s3 (h2) -NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR ^N1 _amino -polyethylene glycol, wherein s1 is an _integer from 1 to _{10 (} e.g., 1 to 6 or 1 to ₄ ), each of _s2 and _s3 is independently an integer from 0 to 10 (e.g., 0 to 4 _, 0 to 6, 1 to 4, 1 to 6 or 1 to 10), and each R ^N1 is independently hydrogen or optionally substituted C _1-6 alkyl; and (21 ⁾ amidine. In some embodiments, each of these groups can be further substituted as described herein.

As used herein, the term "aryl" refers to a monocyclic, bicyclic or polycyclic carbocyclic ring system having one or two aromatic rings, and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, dihydroindenyl, indenyl, and the like, and may be substituted, if necessary, with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: (1) C _1-7 acyl (e.g., carboxyaldehyde); (2) C _1-20 alkyl (e.g., C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkylsulfinyl-C _1-6 alkyl, amino-C _1-6 alkyl, azido-C 1-6 alkyl); (e.g., C _1-6 alkyl, (carboxyaldehyde)-C _1-6 alkyl, halogen-C _1-6 alkyl (e.g., perfluoroalkyl), hydroxyl-C _1-6 alkyl, nitro-C _1-6 alkyl or C _1-6 thioalkoxy-C _1-6 alkyl); (3) C _1-20 alkoxy (e.g., C _1-6 alkoxy, such as perfluoroalkoxy); (4) C _1-6 alkylsulfinyl; (5) C _6-10 aryl; (6) amino; (7) C _1-6 alkane-C _6-10 aryl; (8) azido; (9) C _3-8 cycloalkyl; (10) C _1-6 alkane-C _3-8 cycloalkyl; (11) halogen; (12) C _1-12 heterocyclic group (e.g., C _1-12 heteroaryl); (13) (14) hydroxyl; (15) nitro; (16) C _1-20 thioalkoxy (e.g., C _1-6 thioalkoxy); (17) -(CH ₂ ) _q CO ₂ ^RA' , wherein q is an integer from zero to four, and RA ^' is selected from the group consisting of (a) C _1-6 alkyl, (b) C _6-10 aryl, (c) hydrogen, and (d) C _1-6 alkane- _{C 6-10} aryl; (18) -(CH ₂ ) _q CONRB ^' RC ^' , wherein q is an integer from zero to four and wherein RB ^' and RC ^' are independently selected from the group consisting of (a) hydrogen, (b) C _1-6 alkyl, (c) C _6-10 aryl, and (d) C _1-6 alkane-C (19) -(CH ₂ ) _q SO ₂ ^{RD '} _, wherein q is an integer from zero to four and wherein ^{RD '} is selected from the group consisting of: (a) alkyl, (b) C _6-10 aryl, and (c) alkane-C _6-10 aryl; (20) -(CH ₂ ) _q SO ₂ NR ^{E ' RF '} , wherein q is an integer from zero to four and wherein each of RE ^' and RF ^' is independently selected from the group consisting of: (a) hydrogen, (b) C _1-6 alkyl, (c) C _6-10 aryl, and (d) C _1-6 alkane-C _6-10 aryl; (21) thiol; (22) C _6-10 aryloxy; (23) C _3-8 cycloalkoxy; (24) C _6-10 aryl-C (25) C _1-6 alkoxy; (26) C _2-20 alkenyl; and (27) C _2-20 alkynyl. In some embodiments _, each of these groups may _{be further substituted as described herein. For example, the alkylene of the C 1 -alkaryl or C 1 - alkaryl heterocyclic} group may be further substituted with pendant oxy groups to provide respective aryl and (heterocyclic) acyl substituents.

As used herein, the term "acyl" refers to a group of the general formula -C(O)R, wherein R is an alkyl group or an aryl group. Examples of "acyl" include, but are not limited to, -C(O) _CH3 , -C(O) _{C2H5 ,} and -C(O)Ph.

As used herein, the term "carbonyl" refers to a C(O) group, which may also be represented by C=O.

As used herein, the term "carboxy" means -CO ₂ H.

Unless otherwise specified, as used herein, the term "cycloalkyl" refers to a monovalent saturated or unsaturated and non-aromatic cyclic hydrocarbon radical from three to eight carbons, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl, and the like. When the cycloalkyl includes a carbon-carbon double bond or a carbon-carbon triple bond, the cycloalkyl may be referred to as a "cycloalkenyl" or "cycloalkynyl," respectively. Exemplary cycloalkenyl and cycloalkynyl groups include cyclopentenyl, cyclohexenyl, cyclohexynyl, and the like. The cycloalkyl group may be optionally substituted by: (1) C _1-7 acyl (e.g., carboxyaldehyde); (2) C _1-20 alkyl (e.g., C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkylsulfinyl-C _1-6 alkyl, amino-C _1-6 alkyl, azido-C _1-6 alkyl, (carboxyaldehyde)-C _1-6 alkyl, halogen-C _1-6 alkyl (e.g., perfluoroalkyl), hydroxyl-C _1-6 alkyl, nitro-C _1-6 alkyl, or C _1-6 thioalkoxy-C _1-6 alkyl); (3) C _1-20 alkoxy (e.g., C _1-6 alkoxy, such as perfluoroalkoxy); (4) C _1-6 alkylsulfinyl; (5) C _6-10 aryl; (6) amino; (7) C 1-20 alkyl (8) azido; (9) C _3-8 cycloalkyl; (10) C _1-6 alkane- _{C 3-8} cycloalkyl; (11) halogen; (12) C _1-12 heterocyclic group (e.g., C _1-12 heteroaryl); (13) (C _1-12 heterocyclic group) _{oxy; (14) hydroxyl; (15) nitro; (16) C 1-20 thioalkoxy (e.g., C 1-6 thioalkoxy )} ; (17) -(CH ₂ ) _q CO ₂ ^{RA '} , wherein q is an integer from zero to four, and RA ^' is selected from the group consisting of: (a) C _1-6 alkyl, (b) C _6-10 aryl, (c) hydrogen, and (d) C _1-6 alkane-C 3-8 cycloalkyl. (18) -(CH ₂ ) _q ^{CONRB'RC '} , wherein q is an integer from zero to four and wherein ^RB' and RC ^' are independently selected from the group consisting of: (a) hydrogen, (b) C _6-10 alkyl, (c) C _6-10 aryl, and (d) C _1-6 alkane-C _6-10 aryl; (19) -(CH ₂ ) _q SO ₂ ^RD' , wherein q is _an integer from zero to four and wherein ^RD' is selected from the group consisting of: (a) C _6-10 alkyl, (b) C _6-10 aryl, and (c) C _1-6 alkane-C _6-10 aryl; (20) -(CH ₂ ) _q SO ₂ NR ^{E'RF '} , wherein q is an integer from zero to four and wherein RE ^' and R Each of ^F' is independently selected from the group consisting of (a) hydrogen, (b) C _6-10 alkyl, (c) C _6-10 aryl, and (d) C _1-6 alk-C _6-10 aryl; (21) thiol; (22) C _6-10 aryloxy; (23) C _3-8 cycloalkoxy; (24) C _6-10 aryl-C _1-6 alkoxy; (25) C _1-6 alk-C _1-12 heterocyclic group (e.g., C _1-6 alk-C _1-12 heteroaryl); (26) pendoxy; (27) C _2-20 alkenyl; and (28) C _2-20 alkynyl. In some embodiments, each of these groups may be further substituted as described herein. For example, the alkylene group of a C ₁ -alkaryl or C ₁ -alkheterocycloyl group may be further substituted with pendant oxy groups to provide the respective aryl and (heterocyclo)acyl substituents.

As used herein, the term "halogen" means a halogen selected from bromine, chlorine, iodine or fluorine.

As used herein, the terms "heteroalkyl" and "heteroalkylene" each refer to an alkyl group as defined herein, wherein one or both of the constituent carbon atoms have been replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group may be further substituted with 1, 2, 3, or 4 substituents as described herein for alkyl groups. As defined herein, as used herein, the terms "heteroalkenyl" and "heteroalkynyl" refer to alkenyl and alkynyl groups, respectively, wherein one or both of the constituent carbon atoms have been replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl and heteroalkynyl groups may be further described with 1, 2, 3, or 4 substituents as described herein for alkyl groups.

As used herein, the term "heteroaryl" refers to a subset of heterocyclic groups as defined herein that are aromatic: that is, they contain 4n+2 π electrons within the monocyclic or polycyclic ring system. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. In some embodiments, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents as defined for heterocyclic groups.

As used herein, the term "oxo" refers to =0.

As used herein, the term "polyethylene glycol" refers to an alkoxy chain comprising one or more monomer units, each of which consists of _-OCH2CH2- . _Polyethylene glycol (PEG) is sometimes also referred to as polyethylene oxide (PEO) or polyoxyethylene (POE), and these terms are considered interchangeable for the _purposes of the present invention. For example, polyethylene glycol can have the structure -( _CH2 ) _s2 ( _OCH2CH2 ) _s1 ( _CH2 ) _s3O- , where s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), and each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10). Polyethylene glycol can also be considered to include amino-polyethylene glycol of -NR ^N1 (CH ₂ ) _s2 (CH ₂ CH ₂ O) _s1 (CH ₂ ) _s3 NR ^N1 -, wherein s1 is an integer from 1 to 10 (e.g., 1 to 6 or 1 to 4), each of s2 and s3 is independently an integer from 0 to 10 (e.g., 0 to 4, 0 to 6, 1 to 4, 1 to 6, or 1 to 10), and each ^RN1 is independently hydrogen or optionally substituted C _1-6 alkyl.

As used herein, the term "isomer" means any tautomer, stereoisomer, enantiomer or diastereoisomer of any compound. It is recognized that these compounds may have one or more chiral centers and/or double bonds and therefore exist in the form of stereoisomers, such as diastereoisomers (i.e., geometric E/Z isomers) or diastereoisomers, enantiomers (i.e., (+) or (-)) or cis/trans isomers). Unless otherwise indicated, chemical structures depicted herein include all corresponding stereoisomers, both stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or non-image-isomerically pure) and enantiomeric and stereoisomer mixtures (e.g., racemates). Enantiomers and stereoisomer mixtures of compounds can generally be resolved into their equal component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained by well-known asymmetric synthesis methods to obtain stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts.

As used herein, the term "stereoisomers" refers to all possible different isomeric and conformational forms that a compound may have (e.g., a compound of any formula described herein), specifically all possible stereochemical and conformational isomeric forms of the basic molecular structure, all non-mirror isomers, enantiomers and/or conformational isomers. Some compounds may exist in different tautomeric forms, all of the latter are included within the scope of the present invention.

As used herein, the term "non-mirror isomers" refers to stereoisomers that are not mirror images of each other and are non-superimposable with each other.

As used herein, the term "enantiomer" means each individual optically active form of a compound having an optical purity or enantiomeric excess of at least 80% (i.e., at least 90% for one enantiomer and at most 10% for the other enantiomer), preferably at least 90% and more preferably at least 98% (as determined by standard methods in the art). Other Terms

As used herein, unless otherwise indicated or inferred from the context, the term "about" or "approximately" refers to a ±10% variation from the recited quantitative value (and includes the recited quantitative value itself). For example, unless otherwise indicated or inferred from the context, a dose of about 100 kBq/kg indicates a dose range of 100±10% kBq/kg, i.e., 90 kBq/kg to 110 kBq/kg (inclusive).

As used herein, the term "combination administration", "combination administration" or "co-administration" means that two or more agents are administered to an individual at the same time or within a certain time interval, so that the effects of each agent on the patient can overlap. Therefore, the two or more agents administered in combination do not need to be administered together. In some embodiments, they are administered within 90 days (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2 or 1 day), within 28 days (e.g., in 14, 7, 6, 5, 4, 3, 2 or 1 day), within 24 hours (e.g., 12, 6, 5, 4, 3, 2 or 1 hour, or within about 60, 30, 15, 10, 5 or 1 minute) of each other. In some embodiments, the administration of the agents is spaced closely enough so that a combined effect is achieved.

As used herein, "administering" an agent to a subject includes contacting cells of the subject with the agent.

The term "cancer" refers to any cancer caused by the proliferation of malignant tumor cells, such as tumors, tumors, carcinomas, sarcomas, leukemias and lymphomas. "Solid tumor cancers" are cancers that include abnormal tissue masses, such as sarcomas, carcinomas and lymphomas. "Hematological cancers" or "fluid cancers" used interchangeably herein are cancers that are present in body fluids, such as lymphomas and leukemias.

As used herein, the term "chelate" refers to an organic compound or a portion thereof that can bind to a central metal or radiometal atom at two or more points.

As used herein, the term "conjugate" refers to a molecule containing a chelating group or its metal complex, a linker group, and, optionally, a therapeutic moiety or a targeting moiety.

As used herein, the term "therapeutic moiety" refers to any molecule or any portion of a molecule that confers a therapeutic benefit. In some embodiments, the therapeutic moiety is a protein or polypeptide, e.g., an antibody, an antigen-binding fragment thereof. In some embodiments, the therapeutic moiety is a small molecule.

As used herein, the term "targeting moiety" refers to any molecule or any portion of a molecule that binds to a given target. In some embodiments, the targeting moiety is a protein or polypeptide, such as an antibody or antigen-binding fragment thereof, a nanobody, an affibody, or a consensus sequence from a fibronectin type III domain. In some embodiments, the targeting moiety is a peptide or a small molecule.

As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, and tautomers of the structures depicted herein.

The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers (such as enantiomers and diastereoisomers) are contemplated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are carefully considered in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described herein and may be isolated as a mixture of isomers or in separated isomeric forms.

The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond for an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactam pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of heterocyclic systems, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

In various places in this specification, substituents of the compounds of the present invention are disclosed in groups or ranges. Specifically, the present invention is intended to include every individual subcombination of the members of these groups and ranges. For example, specifically, the term "C _1-6 alkyl" is intended to disclose methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl individually. Phrases of the form "optionally substituted X" (e.g., optionally substituted alkyl) herein are intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). It is not intended to mean that the feature "X" (e.g., alkyl) itself is optional.

As used herein, the terms "reduce", "decrease", "increase", "increase" or "lower", "lower" (e.g., when referring to a treatment outcome or effect) have the meaning relative to a reference level. In some embodiments, the reference level is a level measured by using the method with a control in an experimental animal model or clinical trial. In some embodiments, the reference level is the level in the same individual before treatment or at the beginning of treatment. In some embodiments, the reference level is the average level in a population not treated with the treatment method.

As used herein, the term "effective amount" of an agent (e.g., any of the aforementioned compounds or conjugates) is an amount sufficient to achieve beneficial or desired results (such as clinical results), and thus "effective amount" depends on the context in which it is used.

As used herein, the term "pharmaceutical composition" means a composition containing a compound described herein formulated with a pharmaceutically acceptable formulation. In some embodiments, the pharmaceutical composition is manufactured or sold as part of a therapeutic regimen for treating a disease in a mammal with approval by a governmental regulatory agency. The pharmaceutical composition can be formulated, for example, for oral administration in a unit dosage form (e.g., tablets, capsules, capsules, encapsulates, or syrups); for topical administration (e.g., as an ointment, gel, lotion, or cream); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.

As used herein, "pharmaceutically acceptable excipients" refers to any ingredient other than the compounds described herein that is non-toxic and non-inflammatory in a patient (e.g., a vehicle that can suspend or dissolve the active compound). Excipients may include, for example: anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming or coating agents, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radioprotectants, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Exemplary excipients include, but are not limited to, ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic acid), calcium stearate, cross-linked carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, citric acid, cross-linked povidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, magnesium stearate, maltitol, mannitol, methylcellulose, Thiamine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, wormwood, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol.

As used herein, the term "pharmaceutically acceptable salt" means salts of the compounds described herein that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation or allergic reaction, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (P.H. Stahl and C.G. Wermuth, eds.), Wiley-VCH, 2008. Such salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

The compounds may have ionizable groups so as to be able to prepare pharmaceutically acceptable salts. Such salts may be acid addition salts involving inorganic or organic acids or, in the case of acidic forms of the compounds, may be prepared from inorganic or organic bases. Typically, the compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid or tartaric acid for the formation of acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines for the formation of basic salts. Methods for preparing suitable salts are well recognized in the art.

Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrosulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyprolate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, glucoheptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, apple acid salt, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bis(hydroxynaphthoate), pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartaric acid, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkaline metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts, and non-toxic ammonium salts, quaternary ammonium salts, and amine cations, including but not limited to ammonium salts, tetramethylammonium salts, tetraethylammonium salts, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

As used herein, the term "radiopharmaceutical" or "radioconjugate" refers to any compound or conjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.

As used herein, the term "radionuclide" refers to an atom that is capable of undergoing radioactive decay (e.g., ³ H, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³⁵ S, ⁴⁷ Sc, ⁵⁵ Co, ⁶⁰ Cu, ⁶¹ Cu, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸⁹ Zr, ⁸⁶ Y, ⁸⁷ Y, ⁹⁰ Y, ⁹⁷ Ru, ⁹⁹ Tc, ^99m Tc, ¹⁰⁵ Rh, ¹⁰⁹ Pd, ¹¹¹ In, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹⁴⁹ Pm, ¹⁴⁹ Tb, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁷⁷ Lu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁹⁸ Au, ¹⁹⁹ Au, ²⁰³ Radionuclides may also be used to describe radionuclides (e.g., ²¹¹ Pb, 212 At, ²¹² Pb, ²¹² Bi, ²¹³ Bi, ²²³ Ra, ²²⁵ Ac, ²²⁷ Th, ²²⁹ Th, ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁸² Rb, ^117m Sn, or ²⁰¹ Tl). The terms radionuclide, radioisotope, or radioisotope may also be used to describe radionuclides. Radionuclides can be used as detectors. ¹⁷⁷ Sm, 178 Tb, 179 Tb, 200 Rb, ^{212 Rb} , ²¹³ Sr, ²¹⁴ Rb, ²¹⁵ Rb-1, ²¹⁶ Rb-2, ^{217 Rb-3, 218 Rb-4, 219 Rb-5, 220 Rb - 6 , 221 Rb - 7} , ²²² Rb ^-8 , ²²³ Rb-9, ²²⁴ Rb-1, ^{225 Rb-1, 226 Rb-1, 227 Rb - 1 , 228 Rb - 2 , 229 Rb} -3, ^{230 Rb} -3, ²³¹ Rb ^{- 3 203} Pb, ²¹¹ At, ²¹² Pb, ²¹² Bi, ²¹³ Bi, ²²³ Ra, ²²⁵ Ac, ²²⁷ Th and ²²⁹ Th.

As used herein and as is well known in the art, "treatment" of a disorder or condition (e.g., a disorder described herein, such as cancer) is an approach for obtaining beneficial or desired results (e.g., clinical results). Beneficial or desired results may include, but are not limited to, a reduction or improvement in one or more symptoms or conditions; a reduction in the extent of the disease, disorder, or condition; stabilization (i.e., not worsening) of the disease, disorder, or condition; prevention of the spread of the disease, disorder, or condition; delay or slowing the progression of the disease, disorder, or condition; amelioration or alleviation of the disease, disorder, or condition; and relief (whether partial or total), whether detectable or undetectable. In the context of cancer treatment, "improvement" may include, for example, reducing the incidence of metastasis, reducing tumor size, reducing tumor vascularization, and/or reducing the growth rate of a tumor. "Reducing" a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are reduced and/or the time course of progression is slowed or prolonged compared to the extent or time course in the absence of treatment. Compounds

The present invention relates in part to compounds that are radiopharmaceuticals. In some embodiments, the compounds of the present invention are selected from the group consisting of the compounds identified in Table 1. Table 1. Compound Structure Compound A Compound B Compound C Compound D Compound E Compound F Compound G Compound H Compound I Compound J Compound K Compound L Compound M Compound N Chelating agents

The compounds of formula I contain a chelating moiety or chelating agent.

As disclosed herein, the chelating agent can be selected from the group consisting of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (1R,4R,7R,10R)-α,α',α",α'"-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTAM (1,4,7,10-tetra(aminomethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid), DOTA-GA anhydride (2,2',2"-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid), DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid)), DOTMP (1,4,6,10-tetraazacyclodecane-1,4,7,10-tetramethylenephosphonic acid, DOTA-4AMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(acetamido-methylenephosphonic acid), CB-TE2A (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), NODA-GA (1,4,7-triazacyclononane-4,7-diacetic acid-1-[2-pentanedioic acid]), NOTP (1,4,7-triazacyclononane-1,4,7-tri(methylenephosphonic acid), TETPA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrapropionic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), HEHA (1,4,7,10,13,16-hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid), PEPA (1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N''',N''''-pentaacetic acid), H ₄ octapa (N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid), H ₂ dedpa (1,2-[[6-(Carboxy)-pyridin-2-yl]-methylamino]ethane), H ₆ phospa (N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridin-2-yl]-methyl-1,2-diaminoethane), TTHA (triethylenetetramine-N,N,N',N",N''',N'''-hexaacetic acid), DO2P (tetraazacyclododecanedimethanephosphonic acid), HP-DO3A (hydroxypropyltetraazacyclododecanetriacetic acid), EDTA (ethylenediaminetetraacetic acid), deferoxamine, DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (diethylenetriaminepentaacetic acid-bismethylamide) and porphyrin.

In certain embodiments, the chelating agent is selected from DOTA, DOTA-GA, NOTA, NODA-GA, NODA-SA, DTPA, TETA, EDTA, TRITA, CDTA and DFO, which are defined as follows: DOTA represents 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA-GA or DOTAGA as used herein represents 1,4,7,10-tetraazacyclododecane, 1-(pentanedioic acid)-4,7,10-triacetic acid, NOTA represents 1,4,7-triazacyclononanetriacetic acid, NODA-GA or NODAGA as used herein represents 1,4,7-triazacyclononane-N-pentanedioic acid-N',N"-diacetic acid, NODA-SA represents 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid, DTPA stands for diethylenetriaminepentaacetic acid, TETA stands for 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid, EDTA stands for ethylamine-N,N'-tetraacetic acid, TRITA stands for 1,4,7,10-tetraazacyclotridecane-l,4,7,10-tetraacetic acid, CDTA stands for trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, DFO represents a desferal or desferrioxamine type group of a chelating agent, a non-limiting example of which is named N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylaminomethyl]-propionyl}-hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide, and has the following chemical structure:

In certain embodiments, the chelating agent is selected from DOTA, DOTAGA, NOTA and NODAGA.

In certain embodiments, the chelating agent is DOTAGA and the compound has the structure of Formula II: (II), wherein each of the variables X, Y, n, ^Z1 and ^Z2 is as defined above in the invention section.

In some embodiments, the chelating agent is represented by the variable W. In some embodiments, W is selected from the group consisting of: , , and . Radionuclides

The present invention includes radiopharmaceuticals each comprising a radionuclide. Examples of suitable radionuclides include, but are not limited to, ⁴³ Sc, ⁴⁴ Sc, ⁴⁷ Sc, ⁵⁵ Co, ⁶⁰ Cu, ⁶¹ Cu, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁸² Rb, ⁸⁶ Y, ⁸⁷ Y, ⁸⁹ Zr, ⁹⁰ Y, ⁹⁷ Ru, ⁹⁹ Tc, ^99m Tc, ¹⁰⁵ Rh, ¹⁰⁹ Pd, ¹¹¹ In, ^117m Sn, ¹³³ La, ¹³⁴ Ce, ¹⁴⁹ Pm, ¹⁴⁹ Tb, ¹⁵³ Sm, ¹⁵² Tb, ¹⁵⁵ Tb, ¹⁶¹ Tb, ¹⁶⁶ Ho, ¹⁷⁷ Lu, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁹⁸ Au, ¹⁹⁹ Au, ²⁰¹ Tl, ²⁰³ Pb, ²¹¹ At, ²¹² Pb, ²¹² Bi, ²¹³ Bi, ²²³ Ra, ²²⁵ Ac, ²²⁷ Th and ²²⁹ Th.

In some embodiments, the radionuclide is selected from the group consisting of ⁶⁴ Cu, ⁶⁷ Cu, ⁶⁸ Ga, ⁹⁰ Y, ¹¹¹ In, ¹⁴⁹ Tb, ¹⁵³ Sm, ¹⁷⁷ Lu, ²¹¹ At, ²¹² Bi, ²¹² Pb, ^{213 Bi, 223 Ra} , ²²⁵ Ac, and ²²⁷ Th.

In some embodiments, the radionuclide is ⁶⁸ Ga, ⁸⁹ Zr, ⁹⁰ Y, ¹¹¹ In, ¹⁷⁷ Lu, or ²²⁵ Ac. In certain embodiments, the radionuclide is ¹⁷⁷ Lu or ²²⁵ Ac.

In some embodiments, the radionuclides used herein are beta emitting radionuclides, such as ¹⁷⁷ Lu. In some embodiments, the radionuclides used herein are alpha emitting radionuclides, such as ²²⁵ Ac. Linkers

The compounds of the present invention comprise a unique linker as shown in the structure of Formula I, which comprises , wherein X is absent or C=O; Y is independently O or NR, R is H, alkyl, aryl or acyl; n is an integer from 0 to 5 (inclusive); ^Z1 and ^Z2 are independently absent or an amino acid unit.

The term "amino acid unit" described herein refers to one or more organic moieties each formed from amino acids (e.g., natural amino acids or non-natural amino acids). Typically, an amino acid unit is formed as shown below: wherein R ² represents an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, each of which may be substituted with a suitable substituent described herein (e.g., -C(O)OH, -NH ₂ , -NH ₃ +, -NH(CNH ₂ ⁺ )NH ₂ ) as required; or, R ² together with the -NH ₂ group in the amino acid forms a heterocyclic ring.

In some embodiments, the amino acid unit refers to an organic moiety formed by aspartic acid (Asp), glutamine (Glu), 2,4-diaminobutyric acid (Dab), 2,3-diaminopropionic acid (Dap), lysine (Lys) or arginine (Arg), which have the structures shown below: .

In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit comprises an organic moiety formed by aspartic acid (Asp), for example, having the structure shown (including stereoisomers thereof) .

In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit is formed by glycine (Gly), for example, having the structure .

In some embodiments, the compound of formula I or formula II is characterized in that the amino acid unit is formed by glutamic acid (Glu), for example, having the structure shown below (including its stereoisomers): .

In some embodiments, the amino acid unit refers to a fragment comprising a plurality of organic moieties formed from glutamine, glutamine and arginine, which have the structures shown below, including all stereoisomers thereof: .

In some embodiments, the compound of formula I or formula II is characterized in that X is C═O.

In some embodiments, the compound of Formula I or Formula II is characterized in that n is 1, 2, 3, 4 or 5. In certain embodiments, n is 4 or 5.

In some embodiments, the compound of Formula I or Formula II is characterized in that each of Z ¹ and Z ² is absent.

In some embodiments, the compound of Formula I or Formula II is characterized in that each of Z ¹ and Z ² is absent, X is C=O, Y is each independently O or NH, and n is 0, 1, 2, 3, 4 or 5. Exemplary linkers include, but are not limited to, the following: , , , , and , each of which may be substituted with a suitable substituent described herein as necessary.

In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z ¹ is an amino acid unit, and Z ² is absent. Representative exemplary compounds are one of the following: and .

In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z ¹ is absent, and Z ² is an amino acid unit. Representative exemplary compounds are one of the following: and .

In some embodiments, the compound of Formula I or Formula II is characterized in that X is (C=O)NH, n is 4 or 5, and each of ^Z1 and ^Z2 is absent. Representative exemplary compounds are one of the following: and .

In some embodiments, the compound of Formula I or Formula II is characterized in that X is C=O, n is 4 or 5, Z ¹ is absent, and Z ² is (C=O)NH(CH ₂ CH ₂ )NH. Representative exemplary compounds are one of the following: and .

In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent, n is 0, Z ¹ is absent, and Z ² is an amino acid unit. Therefore, the linker of these compounds will be: , wherein R ² represents an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, each of which may be substituted with a suitable substituent as described herein as necessary; or, R ² together with the -NH ₂ group in the amino acid forms a heterocyclic ring.

Representative exemplary compounds are one of the following: and .

In some embodiments, the compound of Formula I or Formula II is characterized in that X is absent, n is 0, and each of ^Z1 and ^Z2 is absent. Representative exemplary compounds are one of the following: and . Individual

In some methods disclosed herein, a therapy (e.g., comprising a therapeutic agent) is administered to a subject. In some embodiments, the subject is a mammal, such as a human.

In some embodiments, the individual has cancer or is at risk of developing cancer. For example, the individual may have been diagnosed with cancer. The cancer may be a primary cancer or a metastatic cancer. The individual may have cancer at any stage, such as stage I, stage II, stage III, or stage IV, with or without lymph node involvement, and with or without metastasis. The compositions provided by the present invention can prevent or reduce further growth of the cancer and/or otherwise improve the cancer (e.g., prevent or reduce metastasis). In some embodiments, the individual does not have cancer but has been determined to be at risk of developing cancer, for example, due to the presence of one or more risk factors, such as environmental exposure, the presence of one or more genetic mutations or variants, family history, etc. In some embodiments, the individual has not yet been diagnosed with cancer.

In some embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer. Administration and Dosage Effective Dose

The present invention provides methods of using the compounds of formula I to treat clinical indications manifesting HSP90, and the compounds are administered to a subject (eg, a human) in a therapeutically effective amount for such treatment.

The present invention also encompasses combination therapies, in which the amount of each therapeutic agent may or may not be therapeutically effective by itself. In some embodiments, a therapeutic combination as disclosed herein is administered to a subject in a manner (e.g., dosage and duration) sufficient to cure or at least partially arrest the symptoms of a disease and its complications. In the context of monotherapy ("monotherapy"), an amount sufficient to achieve this purpose is defined as a "therapeutically effective amount," an amount of a compound sufficient to substantially improve at least one symptom associated with a disease or medical condition. The "therapeutically effective amount" generally varies depending on the therapeutic agent. For known therapeutic agents, the relevant therapeutically effective amount may be known or readily determined by those skilled in the art.

For example, in the treatment of cancer, an agent or compound that reduces, prevents, delays, inhibits or suppresses any symptom of the disease or disorder will be therapeutically effective. A therapeutically effective amount of an agent or compound need not cure the disease or disorder, but will provide treatment for the disease or disorder such that the onset of the disease or disorder in an individual is delayed, hindered or prevented, or symptoms of the disease or disorder are ameliorated, or the duration of the disease or disorder is altered, or is, for example, less severe, or recovery is accelerated. For example, a treatment may be therapeutically effective if it causes cancer regression or slows the growth of cancer.

Dosage regimens effective for these uses (e.g., the amount of each therapeutic agent, the relative duration of treatment, etc.) may depend on the severity of the disease or condition and the weight and general condition of the individual. For example, a therapeutically effective amount of a particular composition comprising a therapeutic agent administered to a mammal (e.g., a human) can be determined by one of ordinary skill in the art after considering the individual differences in age, weight, and condition of the mammal. Because certain conjugates of the present invention exhibit enhanced ability to target cancer cells and residual cancer, the dosage of these compounds may be lower than the equivalent dosage required for the therapeutic effect of the unconjugated agent (e.g., less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%). Therapeutically effective and/or optimal amounts may also be determined empirically by those skilled in the art. Therefore, lower effective dosages may also be determined by those skilled in the art.

Single or multiple administrations of a radiopharmaceutical or composition (e.g., a pharmaceutical composition comprising a therapeutic agent or radiopharmaceutical) can be performed in a dose and mode selected by the attending physician. The dose and administration schedule can be determined and adjusted based on the severity of the individual's disease or condition, which can be monitored throughout the course of treatment according to methods commonly practiced by clinicians or those described herein.

As provided above, the radiopharmaceutical compounds of the present invention can be administered in combination with another therapeutic agent. In the combination therapy methods disclosed herein, the first and second therapeutic agents can be administered to the individual sequentially or simultaneously. For example, a first composition comprising a first therapeutic agent and a second composition comprising a second therapeutic agent can be administered to the individual sequentially or simultaneously. Alternatively, a composition comprising a combination of the first therapeutic agent and the second therapeutic agent can be administered to the individual.

In some embodiments, the radiopharmaceutical is administered in a single dose. In some embodiments, the radiopharmaceutical is administered more than once, i.e., in multiple doses. When the radiopharmaceutical is administered more than once, the doses administered each time may be the same or different.

In some embodiments, a composition (e.g., a composition comprising a radiopharmaceutical) is administered for radiation therapy planning or diagnostic purposes. When administered for radiation therapy planning or diagnostic purposes, the composition can be administered to a subject in a diagnostically effective dose and/or in an amount effective to determine a therapeutically effective dose. In some embodiments, a first dose of a conjugate disclosed herein or a composition thereof (e.g., a pharmaceutical composition) is administered in an amount effective for a radiation therapy plan, followed by administration of a combination therapy comprising a conjugate as disclosed herein and another therapeutic agent.

Pharmaceutical compositions comprising one or more agents (e.g., radiopharmaceuticals) can be formulated for use in various drug delivery systems according to the methods and systems disclosed herein. One or more physiologically acceptable excipients or carriers may also be included in the composition for proper formulation. Examples of suitable formulations are found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th edition 1985. For a brief review of methods for drug delivery, see, e.g., Langer (Science 249:1527-1533, 1990). Formulations

The pharmaceutical composition can be formulated for parenteral, intranasal, topical, oral or local administration, such as by transdermal means, for preventive and/or therapeutic treatment. The pharmaceutical composition can be administered parenterally (e.g., by intravenous, intramuscular or subcutaneous injection), or by oral administration, or by topical application or intraarticular injection at an area affected by a vascular or cancer condition. Additional examples of routes of administration include intravascular, intraarterial, intratumoral, intraperitoneal, intraventricular, epidural, and nasal, ocular, intrascleral, intraorbital, rectal, topical or aerosol inhalation administration. Also expressly contemplated is sustained release administration, by means such as depot injections or erodible implants or compositions. Suitable compositions include compositions comprising a pharmaceutical agent (e.g., a compound as disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, such as water, buffered water, saline or PBS, etc., for parenteral administration. The composition may contain pharmaceutically acceptable auxiliary substances that approximate physiological conditions, such as pH adjusters and buffers, tonicity adjusters, wetting agents or detergents, etc. In some embodiments, the composition is formulated for oral delivery; for example, the composition may contain inert ingredients, such as binders or fillers for formulation of unit dosage forms, such as tablets or capsules. In some embodiments, the composition is formulated for topical administration; for example, the composition may contain inert ingredients such as solvents or emulsifiers for formulation of creams, ointments, gels, pastes, or eye drops.

The composition can be sterilized, for example, by conventional sterilization techniques, or aseptically filtered. The aqueous solution can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier before administration. The pH of such preparations will generally be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 6 and 7, such as 6 to 6.5. In some embodiments, the composition in solid form is packaged in multiple single dosage units, each containing a fixed amount of one or more of the above-mentioned agents, such as in a sealed package of tablets or capsules. In some embodiments, the composition in solid form is packaged in a flexible container, such as a squeezable tube designed for topical application as a cream or ointment. Synthesis of Radiopharmaceuticals Comprising Compounds of Formula I

The compound of formula I comprises a binder that targets HSP90, which can be radiolabeled with a radionuclide, such as indium-111 ( ^111In ), indium-177 ( ^177Lu ) or indium-225 ( ^225Ac ) to form a radiopharmaceutical chelated with a radionuclide. The synthesis of the compound of formula I or its radiopharmaceutical chelated with a radionuclide can be referred to WO 2020/205948. The following is a synthetic scheme or draft that can be followed to synthesize the corresponding compound. A person of ordinary skill will be able to prepare the compounds depicted herein and their structurally similar analogs (for example, compounds with different chelators, such as DOTA, NOTA and NODA-GA) based on the present invention provided herein and the knowledge in the field.

Synthesis Scheme 1.

Synthesis Scheme 2.

Synthesis Scheme 3.

Synthesis Scheme 4.

Synthesis Scheme 5.

Synthesis Scheme 6.

Synthesis Scheme 7. Materials and Analytical Assays The analytical assays used to characterize compounds of Formula I are provided below.

Ac) was supplied by the US Department of Energy Isotope Program in the Office of Science for Nuclear Physics. ^Lu ) was received from ^{ITG Isotope Technologies Garching GmbH. Indium-111 (111In )} was supplied by BWXT.

RadioTLC was performed using a Bioscan AR-2000 imaging scanner on iTLC-SG glass microfiber chromatography paper (Agilent Technologies, SGI0001) or iTLC-SA glass microfiber chromatography paper (Agilent Technologies, A120B12).

Radio-HPLC was performed using a Waters system comprising a Waters 1525 binary HPLC pump, a Waters 2489 UV/Vis detector (monitoring at 254 and 214 nm), a Bioscan flow-counter radioactivity detector (FC-3300), and a reversed phase (C18) column. Alternatively, the analysis was performed using a Waters Acquity UPLC system comprising a Waters Acquity binary solvent manager, a Waters Acquity sample manager, a Waters Acquity column manager (column temperature 30°C), a Water Acquity photodiode array detector (detecting at 254 and 214 nm), a Bioscan flow-counter radioactivity detector (FC-3300), and a reversed phase (C18) column.

Analytical HPLC-MS was performed using a Waters Acquity HPLC-MS system comprising a Waters Acquity binary solvent manager, a Waters Acquity sample manager, a Waters Acquity column manager (column temperature 30°C), a Waters Acquity photodiode array detector (monitoring at 254 nm and 214 nm), a Waters Acquity TQD with electrospray ionization, and a Waters Acquity BEH C18, 2.1 x 50 mm (1.7 µm) column. Preparative HPLC was performed using a Waters HPLC system consisting of a Waters 1525 binary HPLC pump, a Waters 2489 UV/Vis detector (monitoring at 254 nm and 214 nm), and a Waters XBridge Preparative C18 19 x 100 mm (5 µm) column.

HPLC elution method 1: Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm) column; mobile phase A: H ₂ O (0.1% v/v TFA); mobile phase B: acetonitrile (0.1% v/v TFA); flow rate = 0.3 mL/min; wavelength = 214, 254 nm; initial = 90% A, 8 min = 0% A, 10 min = 0% A, 11 min = 90% A, 12 min = 90% A.

HPLC elution method 2: Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm) column; mobile phase A: H ₂ O (0.1% v/v TFA); mobile phase B: acetonitrile (0.1% v/v TFA); flow rate = 0.3 mL/min; wavelength = 214, 254 nm; initial = 90% A, 3 min = 0% A, 3.5 min = 0% A, 4 min = 90% A, 5 min = 90% A.

HPLC elution method 3: Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm) column; mobile phase A: H ₂ O (0.1% v/v formic acid); mobile phase B: acetonitrile (0.1% v/v formic acid); flow rate = 0.3 mL/min; wavelength = 214, 254 nm; initial = 90% A, 3 min = 0% A, 3.5 min = 0% A, 4 min = 90% A, 5 min = 90% A.

HPLC elution method 4: Waters Acquity BEH C18 2.1 x 50 mm (1.7 µm) column; mobile phase A: H ₂ O (0.1% v/v formic acid); mobile phase B: acetonitrile (0.1% v/v formic acid); flow rate = 0.3 mL/min; wavelength = 214, 254 nm; initial = 90% A, 8 min = 0% A, 10 min = 0% A, 11 min = 90% A, 12 min = 90% A.

HPLC Elution Method 5 (RadioHPLC): Phenomenex Gemini 5 µm C18 110 Å, LC column 150 x 4.6 mm; Mobile Phase A: H ₂ O (0.1% v/v TFA); Mobile Phase B: Acetonitrile (0.1% v/v TFA); Flow Rate = 1.0 mL/min; Wavelength = 214, 254 nm; Initial = 100% A, 2 min = 100% A, 10 min = 0% A, 12 min = 0% A, 14 min = 100% A, 15 min = 100% A.

HRMS was performed using an Agilent G1969 ESI TOF system. Examples Example 1: Synthesis of (R)-2,2',2''-(10-(20-carboxy-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,17-dioxo-4,7,10,13-tetraoxa-16-azaeicosan-20-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound A) Step 1: Synthesis of (R)-17-oxo-20-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-4,7,10,13-tetraoxo-16-azaheneicosandedioic acid 1-benzyl 21-(tert-butyl) ester (Intermediate 1-A) To a 20 mL flash bottle was added (R)-DOTAGA(tBu) ₄ (500 mg, 0.71 mmol, 1 eq) and a stir bar, then anhydrous dichloromethane (3.6 mL) was added to form a 0.2 M solution. CDI (126 mg, 0.74 mmol, 1.1 eq) was then added and the solution was stirred at room temperature and monitored by HPLC-MS. After 3 h, only ~35% conversion was observed, so the reaction was re-dosed with CDI (70 mg, 0.43 mmol, 0.6 eq) and stirred at room temperature for 18.5 h. At this time, an aliquot of the reaction was checked and found to have the same approximate conversion. The reaction solution was transferred to a second vial containing amino-PEG4-benzyl ester (279 mg, 0.78 mmol, 1.1 eq) in anhydrous dichloromethane (1 mL) and stirred at room temperature. The reaction was monitored by HPLC-MS and ~29% conversion of the product was found after 3 h and by HPLC-MS, the residue was DOTAGA(tBu) ₄ . The reaction was worked up by concentration under vacuum and then resubjected to the reaction conditions by adding the following reagents: anhydrous THF (4.6 mL) and HBTU (803 mg, 2.12 mmol, 3 equiv), at which point the reaction was stirred for 5 min, then DIPEA (0.62 mL) was added and stirred at room temperature (22.5 °C) over the weekend. After 88 h, the reaction was complete and worked up by concentration under vacuum. The crude product was purified by reverse phase C18 column chromatography to afford intermediate 1-A (436 mg, 47%, purity: >96%) as a light yellow viscous solid, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 4.90 min; MS (positive ESI): found m/z 1038.6 [M+H] ⁺ ; C ₅₃ H ₉₂ N ₅ O ₁₅ (Calculated value 1038.6). ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 7.96 (br s, 1H), 7.38-7.31 (m, 5H), 5.11 (s, 2H), 4.62-2.65 (with H ₂ O overlapping multiplets, 43H), 2.60 (t, J = 7.0 Hz, 2H), 2.49-2.43 (m, 1H), 2.43-2.35 (m, 1H), 1.47 (br s, 9H), 1.46 (br s, 9H), 1.42 (br s, 9H), 1.40 (br s, 9H); ¹³ C NMR (176 MHz, DMSO-d ₆ ) δ 171.6, 170.6, 158.3 (TFA, q, J = 35.2 Hz), 136.5, 128.4, 128.0, 127.8, 115.8 (TFA, q, J = 299.2 Hz), 83.8 (br), 81.6 (br), 69.8 (2C), 69.7 (2C), 69.6, 69.1, 66.0, 65.4, 54.5 (br), 53.4 (br), 38.5, 34.7, 31.8 (br), 27.8, 27.7, 27.6 (2C). Step 2: Synthesis of (R)-2,2-dimethyl-4,8-dioxo-5-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-3,12,15,18,21-pentaoxa-9-azatetracosanoic acid (Intermediate 1-B) To a solution of Intermediate 1-A (396 mg, 0.30 mmol, 1 eq) in anhydrous MeOH (4 mL) in a 20 mL vial was added a stir bar and Pd/C, 10% Pd base (32 mg, 0.03 mmol, 0.1 eq). The reaction mixture was degassed and subjected to H 2 O via a balloon (3X). ₂ atmosphere. The reaction was then stirred at room temperature (22 degrees Celsius) and monitored by HPLC-MS. After 18 h, the reaction was filtered through an Acrodisc One (0.2 µm PTFE) syringe filter into a 20 mL flash bottle. The reaction vial was then rinsed with MeOH (4 mL) and this was also filtered into the flash bottle. The crude reaction was then concentrated under reduced pressure to provide 387 mg of a clear film. The crude product was purified by reverse phase C18 column chromatography to provide intermediate 1-B (237 mg, 66%, purity: 99%) as a clear film, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 4.06 min; MS (positive ESI): found m/z 948.7 [M+H] ⁺ ; C ₄₆ H ₈₆ N ₅ O ₁₅ (Calculated value 948.6). ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 4.62-2.60 (with H ₂ O overlapping multiplets, 43H), 2.48-2.45 (m, 1H), 2.44 (t, J = 7.0 Hz, 2H), 2.41-2.35 (m, 1H), 1.45 (br s, 18H), 1.41 (br s, 18H); ¹³ C NMR (176 MHz, DMSO-d ₆ ) δ 172.6, 171.7, 158.2 (TFA, q, J = 33.4 Hz), 116.4 (TFA, q, J = 303.8 Hz), 69.8, 69.7 (2C), 69.6 (2C), 69.1, 66.2, 54.6 (br), 53.7 (br), 38.6, 31.8 (br), 27.8, 27.7 (2C), 27.6. Step 3: Synthesis of 2,2',2''-(10-(2,4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,2-dimethyl-4,8,24-trioxo-3,12,15,18,21-pentaoxazolo-9-azatetracosane-5-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetic acid tert-butyl ester (Intermediate 1-D) To a 20 mL vial was added Intermediate 1-B (14 mg, 15 µmol, 1 eq) followed by 1 portion of anhydrous DMF (1 mL) and a stir bar. The vessel was then charged with HBTU (5.6 mg, 15 µmol, 1 eq.) and finally DIPEA (12.4 µL, 71 µmol, 5 eq.) and stirred at room temperature (22°C) for 5 min. A solution of intermediate 1-C (8 mg, 1 eq.) in anhydrous DMF (1 mL) was then added and the vial containing the intermediate was rinsed with another 1 mL of anhydrous DMF and added to the reaction vessel. The resulting solution was stirred at room temperature (22°C) and monitored by HPLC-MS. After 1 h, the reaction was worked up by concentrating under vacuum. The crude product was purified by reverse phase C18 column chromatography to provide intermediate 1-D (12.4 mg, 96%, purity: 96%), TFA salt as a clear film. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 4.72 min; MS (positive ESI): found m/z 1393.9 [M+H] ⁺ ; C ₇₂ H ₁₁₇ N ₁₀ O ₁₇ (Calculated value 1393.8). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.55 (s, 1H), 6.33 (s, 1H), 4.35-0.92 (with H ₂ O and DMSO overlapping multiplets and a triplet at 0.99 ppm, 97H), 0.99 (t, J = 7.0 Hz, 3H), 0.76 (d, J = 7.0 Hz, 6H). Step 4: Synthesis of (R)-2,2',2''-(10-(21-carboxy-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazaheneicosane-21-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound A) To a 20 mL vial was added intermediate 1-D (10.4 mg, 6.4 µmol, 1 eq) and a stir bar, followed by 2 mL of TFA/TIPS/H ₂ O (95:2.5:2.5 v/v/v). The resulting clear solution was placed in a 37 °C oil bath and the reaction was monitored by HPLC-MS. After 3 h, the reaction was complete and concentrated under air flow. The crude product was purified by reverse phase C18 column chromatography to provide compound A (6.5 mg, 75%, purity: >99%) as a white solid, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.00 min; HRMS (positive ESI): found m/z 1169.6074 [M+H] ⁺ ; C ₅₆ H ₈₅ N ₁₀ O ₁₇ (Calculated value 1169.6089). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.23 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.56 (s, 1H), 6.32 (s, 1H), 4.30 (br d, 2H), 4.05-2.35 (with H ₂ O and DMSO overlapping multiplets, 47H), 1.90-1.80 (br m, 3H), 1.77-1.71 (m, 2H), 1.61-1.55 (m, 3H), 1.11-1.08 (m, 2H), 1.00 (t, J = 7.0 Hz, 3H), 0.98-0.95 (m, 2H), 0.76 (d, J = 7.0 Hz, 6H); ¹³ C NMR (175 MHz, DMSO-d ₆ ) δ 171.7, 168.5, 157.9 (TFA, app q, J = 31.5 Hz), 157.3, 156.2 (2C), 154.4, 147.8, 141.4, 133.2, 129.6, 127.3, 125.8, 125.5, 117.3 (TFA, app q, J = 297.5 Hz), 102.6, 102.5, 69.8 (2C), 69.7 (2C), 69.6, 69.1, 66.9, 53.7, 45.1, 41.7, 41.1, 40.0, 38.6, 37.3, 33.6, 32.9, 32.2, 31.3, 25.3, 22.4, 14.5. Example 2: Synthesis of 2,2',2''-(10-(24-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminomethyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound B) Step 1: Synthesis of 2-oxo-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-6,9,12,15,18,21-hexaoxa-3-azatetracosanoic acid (Intermediate 2-A) To a solution of DOTAtris(tert-butyl ester) (50 mg, 0.09 mmol, 1 eq.) in MeCN (2.0 mL) were added N,N'-disuccinimidyl carbonate (DSC) (32 mg, 0.11 mmol, 1.3 eq.) and pyridine (0.20 mL, 2.5 mmol, 28 eq.). The reaction mixture was stirred at room temperature (22.5°C) and monitored by HPLC-MS. After 70 min, ~80% starting material remained, so the reaction was dosed with HBTU (34 mg, 0.09 mmol, 1 eq) and stirred at room temperature for 10 min. The reaction mixture was then transferred to a second vial containing amino-PEG6-acid (64 mg, 0.17 mmol, 2 eq) in anhydrous DMF (1 mL, limited solubility) and stirred at room temperature. The reaction was monitored by HPLC-MS and worked up after 64 h by concentration under vacuum to provide a clear oil. The crude product was purified by reverse phase C18 column chromatography to provide intermediate 2-A (35 mg, 36%, purity >99%), TFA salt as a clear film. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.70 min; MS (positive ESI): found m/z 908.9 [M+H] ⁺ ; C ₄₃ H ₈₂ N ₅ O ₁₅ (Calculated value 908.6). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 4.20-2.46 (with H ₂ O overlapping multiplet, triplet at 3.57 ppm (J = 7.0 Hz, 2H and DMSO; total 50H), 2.42 (t, J = 7.0 Hz, 2H), 1.44 (br s, 9H), 1.36 (br s, 18H). Step 2: Synthesis of tert-butyl 2,2',2''-(10-(24-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 2-C) To a solution of Intermediate 2-A (30 mg, 26 µmol, 1 eq.) in MeCN (2 mL) were added HBTU (12 mg, 32 µmol, 1.2 eq.) and DIPEA (18 µL, 0.11 mmol, 4 eq.). This was stirred at room temperature (22.5 °C) for 10 min, then intermediate 2-B (22 mg, 32 µmol, 1.2 eq.) was added and the solution was stirred and monitored by HPLC-MS. After 1 h, the reaction was worked up by concentration to dryness under vacuum. The crude product was purified by reverse phase C18 column chromatography to provide intermediate 2-C (35 mg, 77%, purity >99%) as a clear film, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 5.52 min; MS (positive ESI): found m/z 1533.7 [M+H] ⁺ ; C ₈₃ H ₁₂₅ N ₁₀ O ₁₇ (Calculated value 1533.9). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.27-7.26 (m, 8H), 7.19 (d, J = 6.8 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 6.96 (s, 1H), 6.92 (d, J = 8.0 Hz, 2H), 6.67 (s, 1H), 5.01 (s, 2H), 4.88 (s, 2H), 4.27 (d, J = 14.0 Hz, 1H), 3.78 (d, J = 14.0 Hz, 1H), 3.55 (t, J = 7.0 Hz, 2H), 3.49-2.36 (with H ₂ O and DMSO overlapped multiplets, 57H), 1.70-1.63 (m, 1H), 1.52-1.17 (overlapped multiplets with wide 2 singlets at 1.42 ppm and 1.33 ppm, 29H), 1.05-0.98 (m overlapped with triplet at 1.00 ppm, J = 7.0 Hz, total 4H), 0.95 (d, J = 7.0 Hz, 6H), 0.92-0.85 (m, 1H). Step 3: Synthesis of tert-butyl 2,2',2''-(10-(24-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 2-D) To a solution of Intermediate 2-C (28.3 mg, 16.1 µmol, 1 eq) in MeOH (2.5 mL) in a microwave vial was added a stir bar and Pd/C, 10% Pd matrix (7 mg, 6 The reaction mixture was degassed and subjected to H ₂ atmosphere. The reaction was then stirred at room temperature (23 °C) and monitored by HPLC-MS. After 16 h, the reaction was filtered through an Acrodisc PSF syringe filter into a 20 mL flash bottle. The reaction vial was rinsed with MeOH (2 x 1.5 mL) and this was also filtered into the flash bottle. The crude reaction was then concentrated under vacuum to provide 23 mg of a yellow film. The crude product was dissolved in MeOH (2 mL) and purified by SiliaMetS ^® Thiol (SH) metal scavenger resin (200 mg, 40 to 63 µm, loading = 1.46 mmol/g) was rinsed to remove the apparent Pd coordination in a 37 °C oil bath and monitored by HPLC-MS. After 1 h, the reaction was filtered through an Acrodisc PSF syringe filter into a 20 mL scintillation vial. The reaction vial was rinsed with MeOH (2 x 1.5 mL) and this was also filtered into the scintillation vial. The crude reaction was then concentrated under vacuum to provide intermediate 2-D (20.8 mg, 81%, purity >97%) as a clear film, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 4.45 min; MS (positive ESI): found m/z 1354.3 [M+H] ⁺ ; C ₆₉ H ₁₁₃ N ₁₀ O ₁₇ (Calculated value 1353.8). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.55 (s, 1H), 6.32 (s, 1H), 4.30 (br d, J = 14.0 Hz, 1H), 4.20-2.36 (with H ₂ O overlapped multiplet, triplet at 3.57 ppm, J = 7.0 Hz, q at 3.14 ppm, J = 7.0 Hz and DMSO, 60H), 1.76-1.70 (m, 1H), 1.62-1.55 (m, 2H), 1.49 (br s, 9H), 1.34 (br s, 18H), 1.12-1.06 (m, 1H), 1.01-0.92 (m overlapped with triplet at 0.99 ppm, J = 7.0 Hz, total 4H), 0.77 (d, J = 7.0 Hz, 6H). Step 4: Synthesis of 2,2',2''-(10-(2,4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,24-dioxo-6,9,12,15,18,21-hexaoxa-3-azatetracosyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound B) To a 20 mL vial was added intermediate 2-D (18.0 mg, 11.4 µmol, 1 eq) and a stir bar, followed by 2 mL of TFA/TIPS/H ₂ O (95:2.5:2.5 v/v/v). The resulting clear solution was placed in a 37 °C oil bath and the reaction was monitored by HPLC-MS. After 2.5 h, the reaction was complete and subsequently concentrated under vacuum. The crude product was purified by reverse phase C18 column chromatography to provide compound B (4.6 mg, 29%, purity: 99%), TFA salt as a white solid. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.15 min; HRMS (positive ESI): found m/z 1185.6386 [M+H] ⁺ ; C ₅₇ H ₈₉ N ₁₀ O ₁₇ (Calculated value 1185.6402). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.56 (s, 1H), 6.32 (s, 1H), 4.30 (br d, J = 14.0 Hz, 2H), 4.10-2.38 (with H ₂ O and DMSO overlapping multiplets, 57H), 1.76-1.68 (m, 2H), 1.63-1.52 (m, 3H), 1.13-1.07 (m, 1H), 0.99-0.93 (m overlapping with triplet at 0.99 ppm, J = 7.0 Hz, total 4H), 0.77 (d, J = 7.0 Hz, 6H). Example 3: Synthesis of 2,2',2''-(10-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminomethyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,4-dioxo-6,9,12,15,18,21,24,27,30,33,36,39-dodeca-3-azatetradecanoyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound C) Step 1: Synthesis of 2-oxo-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-6,9,12,15,18,21,24,27,30,33,36,39-dodeca-3-azatetradecane-42-oic acid (Intermediate 3-A) To a solution of DOTAtris(tert-butyl ester) (50 mg, 0.09 mmol, 1 eq) in MeCN (2.0 mL) were added N,N′-disuccinimidyl carbonate (DSC) (32 mg, 0.11 mmol, 1.3 eq) and pyridine (0.20 mL, 2.5 mmol, 28 eq). The reaction mixture was stirred at room temperature (22.5 °C) and monitored by HPLC-MS. After 70 min, ~80% starting material remained, so the reaction was dosed with HBTU (34 mg, 0.09 mmol, 1 eq) and stirred for 10 min at room temperature. The reaction mixture was then transferred to a second vial containing amino-PEG12-acid (81 mg, 0.13 mmol, 1.5 eq) in anhydrous DMF (1 mL, limited solubility) and stirred at room temperature. The reaction was monitored by HPLC-MS and worked up after 64 h by concentration under vacuum to provide a clear oil. The crude product was purified by reverse phase C18 column chromatography to provide intermediate 3-A (49 mg, 32%, purity 80%), TFA salt as a clear film. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.70 min; MS (positive ESI): found m/z 1173.2 [M+H] ⁺ ; C ₅₅ H ₁₀₆ N ₅ O _{twenty one} (Calculated value 1172.7). Step 2: Synthesis of tert-butyl 2,2',2''-(10-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,4-dioxo-6,9,12,15,18,21,24,27,30,33,36,39-dodeca-3-azatetradecanoyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 3-B) To a solution of Intermediate 3-A (49 mg, 35 µmol, 1 eq) in MeCN (2 mL) was added HBTU (14 mg, 46 µmol, 1.3 equiv), DIPEA (24 µL, 0.14 mmol, 5 equiv) and a stir bar. The reaction was stirred for 10 min at room temperature (22.5°C), then intermediate 2-B (26 mg, 38 µmol, 1.3 equiv) was added and the solution was stirred and monitored by HPLC-MS. After 1 h, the reaction was worked up by concentrating to dryness under vacuum. The crude product was purified by reverse phase C18 column chromatography to provide intermediate 3-B (40 mg, 70%, purity >99%) as a clear film, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 5.40 min; MS (positive ESI): found m/z 1797.9 [M+H] ⁺ ; C ₉₅ H ₁₄₉ N ₁₀ O _{twenty three} (Calculated value 1798.1). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.36-7.26 (m, 8H), 7.19 (d, J = 7.0 Hz, 2H), 7.05 (d, J = 7.0 Hz, 2H), 6.96 (s, 1H), 6.92 (d, J = 7.0 Hz, 2H) 6.67 (s, 1H), 5.01 (s, 2H), 4.88 (s, 2H), 4.27 (br d, J = 14.0 Hz, 1H), 3.78 (br d, J = 14.4 Hz, 1H), 3.55 (t, J = 7.0 Hz, 2H), 3.52-2.37 (with H ₂ O and DMSO overlapped multiplet, 81H), 1.69-1.63 (m, 1H), 1.52-1.38 (m overlapped with br s at 1.42 ppm, 12H), 1.34 (br s, 18H), 1.05-0.98 (m overlapped with triplet at 1.00 ppm, J = 7.0 Hz, total 4H), 0.96 (d, J = 7.0 Hz, 6H). Step 3: Synthesis of tert-butyl 2,2',2''-(10-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,4-dioxo-6,9,12,15,18,21,24,27,30,33,36,39-dodeca-3-azatetradecanoyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 3-C) Intermediate 3-B (33 mg, 0.02 mmol, 1 eq) was added to MeOH (2.5 mmol) in a microwave vial. To a solution in 10 mL of 4% MgCl2 (1% MgCl2) was added a stir bar and Pd/C, 10% Pd matrix (7 mg, 6 μmol, 0.4 eq.). The reaction mixture was degassed and subjected to H ₂ atmosphere. The reaction was then stirred at room temperature (23 °C) and monitored by HPLC-MS. After 16 h, the reaction was filtered through an Acrodisc PSF syringe filter into a 20 mL flash vial. The reaction vial was rinsed with MeOH (2 x 1.5 mL) and this was also filtered into the flash vial. The crude reaction was then concentrated under reduced pressure to provide 30 mg of a light yellow film. The crude mixture was then dissolved in MeOH (3 mL) and precipitated with SiliaMetS ^® Thiol (SH) metal scavenger resin (200 mg, 40 to 63 µm, loading = 1.46 mmol/g) was stirred halfway to remove the Pd coordination in a 50 °C oil bath and monitored by HPLC-MS. After 2 h, the reaction was filtered through an Acrodisc PSF syringe filter into a 20 mL flash vial. The reaction vial was rinsed with MeOH (2 x 2 mL) and this was also filtered into the flash vial. The crude reaction was then concentrated under vacuum. This protocol was repeated with the second half-crude material and combined to provide intermediate 3-C (19.8 mg, 66%, purity >99%) as a clear film, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 4.40 min; MS (positive ESI): found m/z 1618.2 [M+H] ⁺ ; C ₈₁ H ₁₃₇ N ₁₀ O _{twenty three} (Calculated value 1618.0). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.24 (br d, J = 7.0 Hz, 2H), 7.19 (br d, J = 7.0 Hz, 2H), 6.56 (s, 1H), 6.32 (s, 1H), 4.41-2.37 (with H ₂ O overlapped multiplet, d at 3.83 ppm, J = 14.7 Hz, t at 3.57 ppm, J = 7.0 Hz, q at 3.14 ppm, J = 7.0 Hz and DMSO, 85H), 1.75-1.68 (m, 1H), 1.62-1.52 (m, 2H), 1.51-1.04 (overlapped multiplet with br singlet at 1.42, 1.34 and 1.18 ppm, 28H), 1.00-0.92 (overlapped triplet with multiplet at 0.99 ppm, 4H), 0.76 (br d, J = 7.0 Hz, 6H). Step 4: Synthesis of 2,2',2''-(10-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,4-dioxo-6,9,12,15,18,21,24,27,30,33,36,39-dodeca-3-azatetradecanoyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound C) To a 20 mL vial was added intermediate 3-C (18.0 mg, 9.8 µmol, 1 eq) and a stir bar, followed by 2 mL of TFA/TIPS/H ₂ O (95:2.5:2.5 v/v/v). The resulting clear solution was placed in a 37°C oil bath and the reaction monitored by HPLC-MS. After 2.5 h, the reaction appeared to be complete and was worked up by transfer to a 50 mL Falcon tube. The reaction vial was rinsed with TFA (2x0.5 mL) and this was also added to the Falcon tube. The Falcon tube was cooled in an ice bath and then Et ₂ O (pre-cooled in the ice bath) to the 45 mL mark. After 5 min, the flask was centrifuged in the ice bath (5 min, 4°C, 3700 rpm) to provide an off-white pellet. ₂ O layer was poured into a round bottom flask and the pellet was dissolved in ACN/H ₂ O (2 mL, 1:1 v/v) and transferred to a tared 20 mL flash vial. ₂ The Felken tube was rinsed with 5% 4% 2H2O (2x2 mL, 1:1 v/v), added to the scintillation vial and concentrated under vacuum to afford 9 mg of crude product as a clear film. The crude product was purified by reverse phase C18 column chromatography to afford Compound C (6.6 mg, 40%, purity: 97%), TFA salt as a white solid. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.27 min; HRMS (positive ESI): found m/z 1487.7508 [M+K] ⁺ ; C ₆₉ H ₁₁₂ KN ₁₀ O _{twenty three} (Calculated value 1487.7533). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.55 (s, 1H), 6.32 (s, 1H), 4.30 (br d, J = 14.0 Hz, 1H), 4.10-2.37 (with H ₂ O and DMSO overlapping multiplet, 84H), 1.76-1.71 (m, 1H), 1.61-1.54 (m, 2H), 1.13-1.06 (m, 1H), 1.01-0.92 (m overlapping with triplet at 0.99 ppm, J = 7.0 Hz, total 4H), 0.77 (d, J = 7.0 Hz, 6H). Example 4: Synthesis of (R)-2,2',2''-(10-(21-carboxy-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminoformyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazahenedecane-21-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound D) Step 1: Synthesis of 2,2',2''-(10-(1-amino-22,22-dimethyl-16,20-dioxo-3,6,9,12,21-pentaoxa-15-azatricosan-19-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-tributyl triacetate (Intermediate 4-A) In a 20 mL flash bottle, charge (R)-DOTAGA( ^t Bu) ₄ (1.00 g, 1.41 mmol, 1 eq.), amino-PEG4-amine (511 mg, 2.12 mmol, 1.5 eq.), HBTU (607 mg, 1.56 mmol, 1.1 eq.), anhydrous acetonitrile and finally DIPEA (1.24 mL, 7.06 mmol, 5 eq.). The reaction was stirred at room temperature (22 °C) and monitored by HPLC-MS. After 2 h, the reaction was worked up by concentration under vacuum to provide a light yellow oil. The crude product was purified by reverse phase C18 column chromatography to provide intermediate 4-A (448 mg, 26%, purity: >93%) as a clear viscous film, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.63 min; MS (positive ESI): found m/z 919.5 [M+H] ⁺ ; C ₄₅ H ₈₇ N ₆ O ₁₃ (Calculated value 919.6). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 4.40-2.30 (including H ₂ O and DMSO overlapping multiplets, 45H), 1.92-1.80 (br m, 1H), 1.69-1.57 (br m, 1H), 1.44 (br s, 18H), 1.33 (br s, 9H), 1.31 (br s, 9H). Step 2: Synthesis of 2,2',2''-(10-(1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-24,24-dimethyl-1,18,22-trioxo-5,8,11,14,23-pentaoxazolo-2,17-diazapentacosan-21-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetate (Intermediate 4-B) To a solution of Intermediate 4-A (50 mg, 41 µmol, 1 eq) in anhydrous THF (1 mL) and a stirring bar was added DIPEA (28.7 µL, 164 µmol, 4 equiv) and cooled to 0°C, then 4-nitrophenyl chloroformate (8.6 mg, 41 µmol, 1 equiv) was added all at once at 0°C. After addition, the reaction was removed from the ice bath to stir at room temperature (21.5°C), purged with an argon balloon and monitored by HPLC-MS. After 45 min, complete conversion to the nitrophenyl intermediate was observed and intermediate 1-C (24 mg, 46 µmol, 1.1 equiv) was added directly to the reaction, followed by the addition of DIPEA (7.2 µL, 46 µmol, 1.1 equiv) and the reaction was purged with an argon balloon. The reaction was stirred at room temperature and monitored by HPLC-MS. After 1 h, anhydrous DMF (1 mL) was added which resulted in a homogeneous solution and the reaction continued to be stirred at room temperature and monitored by HPLC-MS. After 1 h, the reaction temperature was raised to 50 °C and monitored by HPLC-MS. After 43 h, the reaction was re-dosed with DIPEA (28.7 µL, 164 µmol, 4 equiv), purged with an argon balloon and stirred in a 50 °C bath for another 21 h, which resulted in complete conversion. The reaction was then worked up by concentrating under vacuum to afford a yellow film. The crude product was purified by reverse phase C18 column chromatography to afford intermediate 4-B (26 mg, 38%, purity: >98%), TFA salt as a clear film. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.42 min; MS (positive ESI): found m/z 1408.8 [M+H] ⁺ ; C ₇₂ H ₁₁₈ N ₁₁ O ₁₇ (Calculated value 1408.9). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.24 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 6.56 (s, 1H), 6.35 (s, 1H), 4.38-2.29 (including H ₂ O and DMSO overlapping multiplets, 55H), 1.67-1.59 (m, 2H), 1.52 (br d, J = 12.9 Hz, 2H), 1.50-1.21 (4 overlapping broad singlets, 36H), 1.04-0.94 (m overlapping with t at 0.99 ppm and J = 7.2 Hz, total 5H), 0.75 (d, J = 7.0 Hz, 6H). Step 3: Synthesis of (R)-2,2',2''-(10-(21-carboxy-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,18-dioxo-5,8,11,14-tetraoxa-2,17-diazaheneicosane-21-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound D) To a 20 mL vial was added intermediate 4-B (16.2 mg, 9.7 µmol, 1 eq), a stir bar, and then 2 mL of TFA/TIPS/H ₂ O (95:2.5:2.5 v/v/v). The resulting clear solution was placed in a 37 °C oil bath and the reaction was monitored by HPLC-MS. After 3.5 h, the reaction was complete and concentrated under air flow. The crude product was purified by reverse phase C18 column chromatography to provide compound D (10 mg, 72%, purity: >99%) as a white solid, TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 2.97 min; HRMS (positive ESI): found m/z 1184.6175 [M+H] ⁺ ; C ₅₆ H ₈₆ N ₁₁ O ₁₇ (Calculated value 1184.6198). ¹ H NMR (700 MHz, DMSO-d ₆ + ~10% D ₂ O) δ 7.24 (d, J = 7.0 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 6.55 (s, 1H), 6.33 (s, 1H), 4.10-2.30 (including H ₂ O and DMSO overlapping multiplets, 52H), 1.95-1.77 (m, 3H), 1.68-1.59 (m, 2H), 1.52 (app br d, J = 14.0 Hz, 2H), 1.03-0.97 (m overlapping with triplet at 0.99 ppm, and J = 7.1 Hz, total 5H), 0.76 (d, J = 7.1 Hz, 6H). Example 5: Synthesis of (R)-2,2',2''-(10-(2,2-carboxy-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminoformyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,14,19-trioxo-4,7,10-trioxa-13,15,18-triazadocosan-22-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound E) Step 1: Synthesis of tert-butyl 2,2',2''-(10-(5-((2-aminoethyl)amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetate (Intermediate 5-A): To a 20 mL flash bottle with a stir bar was added (R)-5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanoate-(R)-DOTAGA( ^t Bu) ₄ (1.50 g, 2.09 mmol, 1 eq.), mono-Fmoc ethylenediamine hydrochloride (817 mg, 2.51 mmol, 1.2 eq.), HBTU (900 mg, 2.09 mmol, 1.1 eq.) and then charged with anhydrous acetonitrile (11 mL) and then charged with DIPEA (1.84 mL, 1370 mg, 10.46 mmol, 5 eq.) and stirred at room temperature. The reaction was monitored by HPLC-MS and stopped after 18 h, and the solvent was evaporated under vacuum to give a crude product, which was subjected to Fmoc deprotection. To the crude product dissolved in anhydrous DMF (8 mL), piperidine (2 mL) was added and the resulting clear orange solution was stirred at room temperature. The reaction was stopped after 30 min and the solvent was evaporated. The obtained crude product was purified by RP chromatography to give intermediate 5-A (550 mg, 24%, purity: 90%) as a white solid as TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.55 min; MS (positive ESI): found m/z 743.5 [M+H] ⁺ ; C ₃₇ H ₇₁ N ₆ O ₉ (Calculated value 743.5). ₃₇ H ₇₁ N ₆ O ₉ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 743.5277; measured value: 743.5291. ¹ H NMR (700 MHz, DMSO-d6 + 10% D ₂ O) 4.40 - 4.17 (m, 2H), 3.82 - 3.43 (m, 8H), 3.40 - 2.88 (m, 9H), 2.87 - 2.79 (m, 2H), 2.62 (br s, 2H), 2.60 (br s, 3H), 2.47 - 2.38 (m, 2H), 1.98 - 1.79 (m, 1H), 1.65 (s, 1H), 1.54 - 1.26 (m, 36H). * Not reported by H ₂ O and DMSO shielded protons. Step 2: Synthesis of (R)-14,19-dioxo-22-(4,7,10-tris(2-(t-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-4,7,10-trioxo-13,15,18-triazatricosanediolatoic acid 23-(t-butyl) ester 1-methyl ester (Intermediate 5-B) 2,2',2''-(10-(5-((2-aminoethyl)amino)-1-(t-butoxy)-1,5-dioxopentane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetate tri-t-butyl ester (Intermediate 5-A) (50 mg, 0.07 To a solution of 3-nitrophenyl chloroformate (14.1 mg, 0.07 mmol, 1 eq.) in anhydrous THF (3 mL) and a stir bar was added DIPEA (35.5 µL, 0.20 mmol, 3 eq.) and cooled to 0 °C, followed by the addition of 4-nitrophenyl chloroformate (14.1 mg, 0.07 mmol, 1 eq.) all at once at 0 °C. After addition, the reaction was allowed to warm to room temperature and monitored by HPLC-MS. After 30 min, complete conversion to the nitrophenyl intermediate was observed by HPLC-MS. Methyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (30.4 mg, 0.13 mmol, 2 eq.) dissolved in anhydrous DMF (1 mL) was added to the reaction under nitrogen, followed by the addition of DIPEA (23.6 µL, 0.13 mmol, 2 eq.). Stirring was continued at room temperature, and after 16 hours, the reaction was stopped and concentrated under vacuum, followed by RP chromatography to provide intermediate 5-B as a white solid as a TFA salt (25 mg, 36%, purity: 98%). An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.24 min; MS (positive ESI): found m/z 1004.6 [M+H] ⁺ ; C ₄₈ H ₉₀ N ₇ O ₁₅ (Calculated value 1004.6). ¹ H NMR (700 MHz, DMSO-d6) δ 7.94 (s, 1H), 6.07 (s, 1H), 5.98 (s, 1H), 4.32-3.68 (br s, 15H), 3.62 (t, J = 6.2 Hz, 2H), 3.59 (s, 3H), 3.52 - 3.47 (m, 2H), 3.49 (s, 6H), 3.36 (t, J = 5.8 Hz, 2H), 3.13 (t, J = 5.8 Hz, 2H), 3.09 - 2.92 (m, 6H), 2.54 (t, J = 6.2 Hz, 2H), 2.07 (s, 4H), 1.61 - 1.27 (m, 42H). Step 3: Synthesis of (R)-2,2-dimethyl-4,8,13-trioxo-5-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-3,17,20,23-tetraoxo-9,12,14-triazahexacos-26-anoic acid (Intermediate 5-C) A flask containing Intermediate 5-B (32 mg, 0.03 mmol, 1 eq) was added with THF (2 mL) and water (1 mL) and placed in an ice bath and stirred for 10 min. Anhydrous lithium hydroxide (2.96 mg, 0.12 mmol) was added all at once as a solid, and the reaction was continued in an ice-water bath. The reaction was monitored by HPLC-MS and after 1 h it was warmed to room temperature and stirring was continued overnight. The reaction solution was acidified (pH ~4) with Amberlite IR120 [H], ~200 mg by stirring at room temperature for 10 min and then filtered to remove the resin. The resin was further washed with ACN, MeOH and then the solvent was evaporated under vacuum. The crude product was dissolved in a 1:1 ACN/water/0.1TFA mixture and subjected to freeze drying to yield the crude intermediate 5-C (29 mg, 87%, purity 90%). An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.15 min; MS (positive ESI): found m/z 991.3 [M+H] ⁺ ; C ₄₇ H ₈₈ N ₇ O ₁₅ (Calculated value 990.6). Step 4: Synthesis of tert-butyl 2,2',2''-(10-(26-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2,2-dimethyl-4,8,13,26-tetraoxy-3,17,20,23-tetraoxa-9,12,14-triazacosac-5-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetate (Intermediate 5-D) To a 20 mL flash bottle with a stir bar was added intermediate 5-C (19.9 mg, 0.02 mmol, 1 eq) and DMF (2 mL). The reaction mixture was cooled to 0 °C and DIPEA (13.8 µL, 10.2 mg, 0.08 mmol, 4 eq) was added followed by HBTU (7.7 mg, 0.04 mmol, 1 eq) and stirred at 0 °C for 10 min. The solution was allowed to warm to room temperature and stirred for 30 min and then intermediate 1-C (10 mg, 0.02 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. The reaction was stopped after 2 h and the solvent was evaporated under vacuum to give a crude product which was purified by preparative HPLC to provide intermediate 5-D (21.4 mg, 64%, purity: 99%) as a white solid as a TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 2.39 min; MS (positive ESI): found m/z 1435.4 [M+H] ⁺ ; C ₇₃ H ₁₁₉ N ₁₂ O ₁₇ (Calculated value 1435.9). ₇₃ H ₁₁₉ N ₁₂ O ₁₇ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1435.8811. Measured value: 1435.8833. ¹ H NMR (700 MHz, DMSO-d6) δ 9.82 (br s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 7.97 (br s, 1H), 7.29 - 7.24 (m, 4H), 7.10 (br s, 2H), 6.57 (s, 1H), 6.36 (s, 1H), 6.06 (br s, 1H), 5.97 (br s, 1H), 4.36 (d, J = 13.1 Hz, 1H), 3.98 - 3.74 (m, 12H), 3.61 (t, J = 6.7 Hz, 2H), 3.53 - 3.47 (m, 9H), 3.37 (t, J = 5.7 Hz, 9 (m, 1H), 1.77 (m, 5H), 1.12 (m, 2H), 1.54 (m, 3H), 1.22 (m, 4H), 1.42 (m, 3H), 1.32 (m, 5H), 1.19 (m, 1H), 1.30 (m, 2H), 1.54 (m, 42H), 1.19 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.01 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H). Step 5: (R)-2,2',2''-(10-(2,2-carboxy-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,14,19-trioxo-4,7,10-trioxa-13,15,18-triazadocosan-22-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound E) To a 20 mL flash bottle with a stir bar at room temperature was added intermediate 5-D (37 mg, 0.03 mmol) and 4.5 mL of the deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5. The reaction was warmed to 37 °C by placing on a preheated oil bath at 37 °C and monitored by HPLC-MS. The reaction was stopped after 3 h and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative HPLC to provide Compound E (20 mg, 54%, purity: 99%) as a white solid TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.02 min; MS (positive ESI): found m/z 1211.5 [M+H] ⁺ ; C ₅₇ H ₈₇ N ₁₂ O ₁₇ (Calculated value 1211.6). For C ₅₇ H ₈₇ N ₁₂ O ₁₇ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1211.6307. Measured value: 1211.6330. ¹ H NMR (700 MHz, DMSO-d6) δ 12.98 (s, 3H), 10.65 (s, 1H), 9.83 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 7.87 (s, 1H), 7.26 (s, 4H), 6.57 (s, 1H), 6.37 - 6.34 (m, 1H), 6.18 (s, 1H), 6.05 (s, 1H), 4.36 (d, J = 12.8 Hz, 1H), 4.05 - 3.73 (m, 11H), 3.61 (t, J = 6.8 Hz, 2H), 3.53 - 3.47 (m, 10H), 3.37 (t, J = 5.8 Hz, 2H), 3.22 - 3.10 (m, 5H), 3.07 - 2.99 (m, 4H), 2.96 - 2.87 (m, 3H), 2.60 - 2.51 (m, 4H), 2.46 (td, J = 12.9, 2.9 Hz, 1H), 2.35 (s, 3H), 1.88 (s, 2H), 1.80 - 1.73 (m, 1H), 1.63 (d, J = 12.7 Hz, 1H), 1.59 (d, J = 13.0 Hz, 1H), 1.18 - 1.10 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.0 0.81 (d, J = 6.9 Hz, 6H). *Not reported by H ₂ O and DMSO shielded protons. Example 6: Synthesis of 2,2',2''-(10-((15S,20R)-20-carboxy-15-(carboxymethyl)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,14,17-trioxo-4,7,10-trioxa-13,16-diazaeicosane-20-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound F) Step 1: Synthesis of ((R)-5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-L-aspartic acid 4-(tert-butyl) 1-methyl ester (Intermediate 6-A) To a 20 mL flash bottle with a stir bar was added (R)-DOTAGA ( ^t Bu) ₄ (869 mg, 0.04 mmol, 1 eq), THF (25 mL) and DMF (5 mL). The reaction mixture was cooled to 0 °C and DIPEA (650 µL, 18.7 mg, 0.14 mmol, 3 eq) followed by HBTU (719 mg, 0.04 mmol, 1.5 eq) was added and stirred at 0 °C for 5 min. The solution was allowed to warm to room temperature and stirred for 15 min and then L-aspartic acid 4-(tert-butyl) 1-methyl ester hydrochloride (300 mg, 0.04 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. After 3 h 30 min, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product, which was purified by RP chromatography to afford intermediate 6-A (722 mg, 64%, purity: 98%) as a white solid as TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.60 min; MS (positive ESI): found m/z 886.7 [M+H] ⁺ ; C ₄₄ H ₈₀ N ₅ O ₁₃ (Calculated value 886.6). ¹ H NMR (700 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.11 (s, 2H), 4.58 (q, J = 7.1 Hz, 1H), 4.06 (br s, 8H), 3.63 (s, 3H), 3.35 - 2.93 (m, 8H), 2.65 (dd, J = 16.1, 6.8 Hz, 2H), 2.56 - 2.49 (m, 2H), 1.87 (s, 2H), 1.52 - 1.40 (m, 36H), 1.39 (s, 9H). *Not reported by H ₂ O and DMSO shielded protons. Step 2: Synthesis of (S)-4-(tert-butoxy)-2-((R)-5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanamido)-4-oxobutanoic acid (Intermediate 6-B): A flask containing Intermediate 6-A (400.00 mg, 0.45 mmol, 1 eq.) was dissolved in THF (6 mL) and water (3 mL) and placed in an ice bath and stirred for 15 min. Anhydrous lithium hydroxide (LiOH) (64.87 mg, 2.71 mmol, 6 eq.) was added all at once as a solid, and the reaction was continued in an ice-water bath. The reaction was monitored by HPLC-MS and after 30 min, the major product was observed. After 1 h, the reaction solution was acidified with Amberlite IR120 [H], ~600 mg by stirring at room temperature for 15 min and then filtered to remove the resin. The resin was further washed with acetonitrile, MeOH and the solvent was evaporated under vacuum. The crude product was lyophilized to give intermediate 6-B (394 mg, 95%, purity: 95%) as a white solid and used in the next step without further purification. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.55 min; MS (positive ESI): found m/z 872.5 [M+H] ⁺ ; C ₄₃ H ₇₈ N ₅ O ₁₃ (Calculated value 872.6). ¹ H NMR (700 MHz, DMSO-d6) δ 12.77 (br s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 4.57 (td, J = 7.9, 5.9 Hz, 1H), 3.75 (s, 3H), 3.53 (s, 2H), 3.42 - 3.30 (m, 5H), 3.12 - 3.06 (m, 5H), 2.91 - 2.81 (m, 5H), 2.80 - 2.73 (m, 2H), 2.66 (dd, J = 15.9, 5.9 Hz, 1H), 2.54 - 2.48 (m, 2H), 2.23 - 2.13 (m, 2H), 1.93 - 1.85 (m, 1H), 1.82 - 1.75 (m, 1H), 1.48 - 1.41 (m, 36H), 1.39 (s, 9H). Step 3: Synthesis of (5R,10S)-10-(2-(tert-butoxy)-2-oxoethyl)-2,2-dimethyl-4,8,11-trioxo-5-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-3,15,18,21-tetraoxa-9,12-diazatetracosanoic acid (Intermediate 6-C) To a 20 mL flash bottle with a stir bar was added intermediate 6-B (70 mg, 0.08 mmol, 1 eq) and DMF (3 mL). The reaction mixture was cooled to 0 °C and DIPEA (42 µL, 31.1 mg, 0.24 mmol, 3 eq) was added followed by HBTU (31.1 mg, 0.08 mmol, 1.0 eq) and stirred at 0 °C for 10 min. The solution was allowed to warm to room temperature and stirred for 15 min, and then 4-(tert-butyl)-3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (19.7 mg, 0.08 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. After 1 h 45 min, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product which was purified by RP chromatography to provide intermediate 6-C (70 mg, 66%, purity: 99%) as a white solid as TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.40 min; MS (positive ESI): found m/z 1075.5 [M+H] ⁺ ; C ₅₂ H ₉₅ N ₆ O ₁₇ (Calculated value 1075.7). ₅₂ H ₉₅ N ₆ O ₁₇ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1075.6748; measured value: 1075.6750. ¹ H NMR (700 MHz, DMSO-d6) 8.12 (d, J = 8.4 Hz, 1H), 7.91 (br s, 1H), 7.08 (br s, 1H), 4.59 - 4.49 (m, 1H), 3.75 (s, 1H), 3.61 - 3.57 (m, 2H), 3.52 - 3.45 (m, 10H), 3.39 (dt, J = 6.1, 3.1 Hz, 3H), 3.27 - 3.20 (m, 2H), 3.20 - 3.12 (m, 3H), 3.12 - 3.02 (m, 3H), 2.91 - 2.72 (m, 2H), 2.61 (dd, J = 15.6, 5.4 Hz, 1H), 2.44 (t, J = 6.4 Hz, 2H), 2.41 - 2.29 (m, 1H), 1.93 - 1.70 (m, 2H), 1.50 - 1.39 (m, 36H), 1.38 - 1.36 (m, 9H). * Not reported by H ₂ O and DMSO shielded protons. Step 4: Synthesis of (5R,10S)-10-(2-(tert-butoxy)-2-oxoethyl)-2,2-dimethyl-4,8,11-trioxo-5-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-3,15,18,21-tetraoxa-9,12-diazatetracosano-24-oic acid (Intermediate 6-D) To a 20 mL flash bottle with a stir bar was added intermediate 6-C (40 mg, 0.04 mmol, 1 eq) and 2.5 mL DMF. The reaction mixture was cooled to 0 °C and DIPEA (30.8 µL, 22.8 mg, 0.14 mmol, 4 eq) was added followed by HBTU (13.7 mg, 0.04 mmol, 1 eq) and stirred at 0 °C for 5 min. The solution was allowed to warm to room temperature and stirred for 20 min and then intermediate 1-C (17.9 mg, 0.04 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. After 75 min the reaction was stopped and the solvent was evaporated under vacuum to give a crude product which was purified by RP chromatography to provide intermediate 6-D (36 mg, 57%, purity: 98%) as a white solid as a TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.62 min; MS (positive ESI): found m/z 1520.9 [M+H] ⁺ ; C ₇₈ H ₁₂₆ N ₁₁ O ₁₉ (Calculated value 1520.9). ₇₈ H ₁₂₆ N ₁₁ O ₁₉ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1520.9226; measured value: 1520.9172. ¹ H NMR (700 MHz, DMSO-d6) δ 9.82 (br s, 2H), 8.95 (t, J = 5.9 Hz, 1H), 8.15 (br s, 1H), 7.93 (br s, 1H), 7.29 - 7.23 (m, 4H), 6.57 (s, 1H), 6.36 (s, 1H), 4.61 - 4.47 (m, 1H), 4.41 - 4.27 (m, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.79 - 3.65 (m, 10H), 3.63 - 3.59 (m, 8H), 3.54 - 3.47 (m, 11H), 3.39 (t, J = 7 - 11 (m, 3H), 1.54 - 1.53 (m, 2H), 1.23 - 1.13 (m, 3H), 1.21 - 1.29 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.09 (dd, J = 12.2, 4.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H), 1.20 (dd, J = 12.2, 4.2 Hz, 3H), 1.17 (s, 9H), 1.21 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H), 1.19 (dd, J = 12.2, 4.2 Hz, 3H), 1.23 (m, 2H), 1.08 (m, 1H), 1H), 0.80 (d, J = 6.9 Hz, 6H). Step 5: Synthesis of 2,2',2''-(10-((15S,20R)-20-carboxy-15-(carboxymethyl)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,14,17-trioxo-4,7,10-trioxa-13,16-diazaicosan-20-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound F) To a 20 mL flash bottle with a stir bar at room temperature were added intermediate 6-D (46 mg, 0.03 mmol, 1 eq) and 2.5 mL deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5 (v/v/v). The reaction was warmed to 37 °C by placing on a preheated oil bath at 37 °C and monitored by HPLC-MS. The reaction was stopped after 4 h and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative RP HPLC to provide Compound F as a white solid as TFA salt (10.3 mg, 26%, purity: 99%). An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 3.07 min; MS (positive ESI): found m/z 1240.3 [M+H] ⁺ ; C ₅₈ H ₈₆ N ₁₁ O ₁₉ (Calculated value 1240.6). ₅₈ H ₈₆ N ₁₁ O ₁₉ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1240.6096. Measured value: 1240.6109. ¹ H NMR (700 MHz, DMSO-d6) δ 10.65 (br s, 1H), 9.80 (br s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.89 (q, J = 6.0 Hz, 1H), 7.29 - 7.23 (m, 4H), 6.57 (s, 1H), 6.35 (s, 1H), 4.51 (dtd, J = 15.8, 7.9, 5.7 Hz, 2H), 4.36 (d, J = 13.0 Hz, 1H), 3.87 (d, J = 13.3 Hz, 1H), 3.61 (td, J = 6.7, 1.6 Hz, 2H), 3.52 - 3.47 (m, 20H), 3.42 - 3.35 (m, 2H), 3.28 - 3.19 (m, 1H), 3.19 - 3.11 (m, 6H), 3.09 (s, 1H), 2.96 - 2.86 (m, 5H), 2.65 - 2.57 (m, 2H), 2.56 (tt, J = 7.2, 3.6 Hz, 4H), 2.50 - 2.43 (m, 4H), 2.40 - 2.38 (m, 1H), 1.91 (s, 1H), 1.80 - 1.76 (m, 2H), 1.64 (d, J = 13.0 Hz, 1H), 1.5 J = 12.7 Hz, 1H), 1.14 (qd, J = 12.6, 4.0 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.96 (m, 2H), 0.81 (d, J = 6.9 Hz, 6H). *Four exchangeable protons not observed. Example 7: Synthesis of (R)-2,2',2''-(10-(1-carboxy-4-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminoformyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound G) Step 1: Synthesis of (R)-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)glycine (Intermediate 7-A) To a 20 mL flash bottle with a stir bar was added (R)-DOTAGA ( ^t Bu) ₄ (462.2 mg, 0.66 mmol, 1 eq) and DMF (3 mL). The reaction mixture was cooled to 0 °C and DIPEA (345 µL, 256 mg, 1.98 mmol, 3 eq) was added followed by HBTU (255 mg, 0.66 mmol, 1 eq) and stirred at 0 °C for 10 min. The solution was allowed to warm to room temperature and stirred for 30 min and then glycine (50 mg, 0.66 mmol, 1 eq) was added as a solid. Glycine had poor solubility in the reaction mixture, so TFA (0.3 mL) and pyridine (0.6 mL) were added to the reaction mixture and stirring was continued at room temperature, pH ~5. The reaction was monitored by HPLC-MS. After 3 h 30 min, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product, which was purified by RP chromatography to afford intermediate 7-A as a white solid as a TFA salt (409 mg, 59%, purity: 95%). An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 4.12 min; MS (positive ESI): found m/z 758.4 [M+H] ⁺ ; C ₃₇ H ₆₈ N ₅ O ₁₁ (Calculated value 758.5). ₃₇ H ₆₈ N ₅ O ₁₁ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 758.4910. Measured value: 758.4928. ¹ H NMR (700 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.10 (s, 1H), 4.51-3. 96 (m, 1H), 3.90 - 3.57 (m, 4H), 3.28 (s, 1H), 3.07 (s, 2H), 2.87 (s, 1H), 2.45 (s, 1H), 2.07 - 1.63 (m, 1H), 1.57 - 1.31 (m, 36H). *Not reported by H ₂ O and DMSO shielded protons. Step 2: Synthesis of 2,2',2''-(10-(1-(tert-butoxy)-5-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)amino)-1,5-dioxopentane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)®-triacetic acid tert-butyl ester (Intermediate 7-B) To a 20 mL flash bottle with a stir bar was added Intermediate 7-A (66.2 mg, 0.08 mmol, 1.4 eq) and DMF (3 mL). The reaction mixture was cooled to 0 °C and DIPEA (51.7 μL, 38.4 mg, 0.3 mmol, 5 eq) was added followed by HBTU (23 mg, 0.06 mmol, 1 eq) and stirred at 0 °C for 10 min. The solution was allowed to warm to room temperature and stirred for 15 min and then intermediate 1-C (30 mg, 0.06 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. After 2 h the reaction was stopped and the solvent was evaporated under vacuum to give a crude product which was purified by preparative RP HPLC to provide intermediate 7-B (67 mg, 77%, purity: 98%) as a white solid as a TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 5.21 min; MS (positive ESI): found m/z 1203.4 [M+H] ⁺ ; C ₆₃ H ₉₉ N ₁₀ O ₁₃ (Calculated value 1203.7). ₆₃ H ₉₉ N ₁₀ O ₁₃ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1203.7388. Measured value: 1203.7361. ¹ H NMR (700 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.98 (s, 1H), 7.30 - 7.25 (m, 4H), 7.14 (s, 1H), 6.57 (s, 1H), 6.36 (s, 1H), 4.39 - 4.28 (m, 1H), 3.89 (s, 2H), 3.82 - 3.70 (m, 2H), 3.18 - 3.13 (m, 2H), 3.07 (s, 2H), 2.96 - 2.87 (m, 1H), 2.59 - 2.52 (m, 3H), 2.47 - 2.45 (m, 1H), 1.80 (t, J = 8.1 Hz, 1H), 1.64 (t, J = 15.6 Hz, 2H), 1.49 - 1.37 (m, 36H), 1.21 - 1.07 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.97 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H). * Not reported by H ₂ O and DMSO masked protons. Step 3: Synthesis of (R)-2,2',2''-(10-(1-carboxy-4-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound G) To a 20 mL flash bottle with a stir bar at room temperature was added intermediate 7-B (35 mg, 0.03 mmol) and 4 mL of the deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5 (v/v/v). The reaction was warmed to 37 °C by placing on a preheated oil bath at 37 °C and monitored by HPLC-MS. The reaction was stopped after 3 h and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative RP HPLC to provide Compound G as a white solid as TFA salt (20 mg, 57%, purity: 99%). An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 1.70 min; MS (positive ESI): found m/z 979.3 [M+H] ⁺ ; C ₄₄ H ₆₂ N ₁₀ O ₁₁ (Calculated value 979.4). ₄₄ H ₆₂ N ₁₀ O ₁₁ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 979.4884. Measured value: 979.4885. ¹ H NMR (700 MHz, DMSO-d6) δ 10.62 (br s, 1H), 9.84 (br s, 1H), 8.95 (t, J = 6.0 Hz, 1H), 7.96 (br s, 1H), 7.28 - 7.25 (m, 4H), 6.57 (s, 1H), 6.36 (s, 1H), 4.34 - 4.30 (m, 1H), 4.07 (s, 1H), 3.91 (d, J = 5.6 Hz, 2H), 3.79 (d, J = 13.5 Hz, 2H), 3.50 (m, 13H), 3.16 (app. p, J = 7.0 Hz, 2H), 3.08 (s, 4H), 2.97 δ - 2.86 (m, 3H), 2.60 - 2.51 (m, 3H), 1.92 (br s, 2H), 1.83 - 1.75 (m, 1H), 1.64 (dd, J = 22.7, 12.9 Hz, 2H), 1.19 - 1.13 (m, 1H), 1.03 (t, J = 7.1 Hz, 3H), 1.02 - 0.97 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H). *Four exchangeable protons not observed. Example 8: Synthesis of 2,2',2''-(10-((R)-1-carboxy-4-(((S)-1-carboxy-4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminoformyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-4-oxobutyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound H) Step 1: Synthesis of (S)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-5-oxopentanoate (Intermediate 8-A) To a 20 mL flash bottle with a stir bar was added (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (43 mg, 0.10 mmol, 1 eq) and DMF (3 mL). The reaction mixture was cooled to 0 °C and DIPEA (70 μL, 51.7 mg, 0.40 mmol, 4 eq) was added followed by HBTU (38.7 mg, 0.10 mmol, 1 eq) and stirred at 0 °C for 15 min. The solution was allowed to warm to room temperature and stirred for 20 min and then intermediate 1-C (50 mg, 0.10 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. After 2 h, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product. The crude product was purified by RP chromatography to provide intermediate 8-A (66 mg, 75%, purity: 98%) as a colorless film/solid. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 3.15 min; MS (positive ESI): found m/z 870.9 [M+H] ⁺ ; C ₅₀ H ₅₉ N ₆ O ₈ (Calculated value 871.4). ₅₀ H ₅₉ N ₆ O ₈ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 871.4389; measured value: 871.4396. ¹ H NMR (700 MHz, DMSO-d6) δ 9.80 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.89 (t, J = 6.6 Hz, 2H), 7.73 (t, J = 7.0 Hz, 2H), 7.69 (dd, J = 8.0, 2.9 Hz, 1H), 7.42 (td, J = 7.5, 3.1 Hz, 2H), 7.35 - 7.31 (m, 2H), 7.30 - 7.19 (m, 4H), 6.58 (d, J = 4.1 Hz, 1H), 6.37 (d, J = 1.2 Hz, 1H), 4.39 - 4.21 (m, 4H), 4.00 - 3.92 (m, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.20 - 3.14 (m, 2H), 2.95 - 2.88 (m, 2H), 2.57 - 2.54 (m, 1H), 2.49 - 2.44 (m, 1H), 2.43 - 2.31 (m, 2H), 1.97 - 1.90 (m, 1H), 1.83 - 1.74 (m, 2H), 1.67 - 1.55 (m, 2H), 1.40 (s, 9H), 1.12 - 1.07 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H), 0.99 (td, J = 12.4, 4.3 Hz, 1H), 0.82- 0.78 (m, 6H). *2 exchangeable protons not observed. Step 2: Synthesis of (S)-2-amino-5-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-5-oxopentanoic acid tert-butyl ester (Intermediate 8-B) To a 20 mL flash bottle with a stir bar at room temperature was added Intermediate 8-A (60 mg, 0.07 mmol, 1 eq) followed by 6 mL of a 15% piperidine solution in DMF. The reaction was monitored by HPLC-MS. The reaction was stopped after 1 h and the solvent was evaporated under vacuum to give a crude product. The product was obtained by precipitation with acetonitrile to provide intermediate 8-B (37 mg, 67%, purity: 96%) as a colorless film/solid. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.07 min; MS (positive ESI): found m/z 649.0 [M+H] ⁺ ; C ₃₅ H ₄₉ N ₆ O ₆ (Calculated value 649.4). Step 3: Synthesis of tert-butyl 2,2',2''-(10-((R)-1-(tert-butoxy)-5-(((S)-1-(tert-butoxy)-5-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,5-dioxopentan-2-yl)amino)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 8-C): Add 20% ethyl acetate to a 20% flask with a stirring bar. To a 5 mL flash vial was added (R)-5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (16.5 mg, 0.02 mmol, 1 eq) and DMF (1.5 mL). The reaction mixture was cooled to 0 °C and DIPEA (16.2 µL, 12 mg, 0.09 mmol, 4 eq) was added followed by HBTU (9.2 mg, 0.02 mmol, 1 eq) and stirred at 0 °C for 15 min. The solution was allowed to warm to room temperature and stirred for 20 min and then intermediate 8-B (18.5 mg, 0.02 mmol, 1 eq) as a solution in DMF (0.5 mL) was added. The reaction was stirred at room temperature and monitored by HPLC-MS. After 3 h 30 min, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product, which was purified by RP chromatography to provide intermediate 8-C as a white solid as TFA salt (24 mg, 64%, purity: 97%). An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 5.31 min; MS (positive ESI): found m/z 1331.8 [M+H] ⁺ ; C ₇₀ H ₁₁₁ N ₁₀ O ₁₅ (Calculated value 1331.8). ₇₀ H ₁₁₁ N ₁₀ O ₁₅ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1331.8225. Measured value: 1331.8283. ¹ H NMR (700 MHz, DMSO-d6) δ 9.84 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 8.24 (br s, 1H), 7.31 - 7.25 (m, 4H), 7.10 (br s, 1H), 6.57 (s, 1H), 6.37 (d, J = 1.8 Hz, 1H), 4.37 (d, J = 12.9 Hz, 1H), 4.11 - 4.07 (m, 2H), 3.83 - 3.68 (m, 3H), 3.19 - 3.14 (m, 2H), 3.08 (s, 2H), 2.98 - 2.81 (m, 3H), 2.57 (d, J = 7.0 Hz, 2H), 2.50 - 2.45 (m, 1H), 2.43 (s, 1H), 2.37 - 2.31 (m, 2H), 1.91 - 1.86 (m, 2H), 1.82 - 1.76 (m, 3H), 1.68 - 1.60 (m, 2H), 1.49 - 1.42 (m, 36H), 1.40 (s, 9H), 1.11 (s, 1H), 1.04 (t, J = 7.2 Hz, 3H), 1.02 - 0.97 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H). * Not reported by H ₂ O and DMSO masked protons. Step 3: Synthesis of 2,2',2''-(10-((R)-1-carboxy-4-(((S)-1-carboxy-4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-4-oxobutyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound H) To a 20 mL flash bottle with a stir bar at room temperature was added intermediate 8-C (17 mg, 9.3 µmol, 1 eq) and 2.5 mL of the deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5 (v/v/v). The reaction was warmed to 37 °C by placing on a preheated oil bath at 37 °C and monitored by HPLC-MS. The reaction was stopped after 2 h 30 min and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative RP HPLC to provide compound H as a white solid as TFA salt (10.5 mg, 87%, purity: 99%). An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 1.71 min; MS (positive ESI): found m/z 1051.6 [M+H] ⁺ ; C ₅₀ H ₇₁ N ₁₀ O ₁₅ (Calculated value 1051.5). ₅₀ H ₇₁ N ₁₀ O ₁₅ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1051.5095. Measured value: 1051.5125. ¹ H NMR (700 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.19 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 1.6 Hz, 4H), 6.57 (s, 1H), 6.36 (s, 1H), 4.38 - 4.34 (m, 1H), 4.20 - 4.16 (m, 1H), 3.80 (d, J = 13.5 Hz, 1H), 3.18 - 3.13 (m, 2H), 2.97 - 2.86 (m, 3H), 2.62 - 2.52 (m, 2H), 2.49 - 2.41 (m, 5H), 2.40 - 2.32 (m, 2H), 1.96 - 1.89 (m, 3H), 1.84 - 1.76 (m, 1H), 1.66 (d, J = 12.5 Hz, 1H), 1.59 (d, J = 12.8 Hz, 1H), 1.18 - 1.09 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.98 (m, 1H), 0.81 (d, J = 6.9 Hz, 6H). * Not reported by H ₂ O and DMSO shielded protons. Example 9: Synthesis of 2,2',2''-(10-((R)-1-carboxy-4-(((S)-4-carboxy-1-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminoformyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxobutyl-2-yl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound I) Step 1: Synthesis of ((R)-5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-L-glutamine 5-(tert-butyl) 1-methyl ester (Intermediate 9-A) To a 20 mL flash bottle with a stir bar was added (R)-DOTAGA ( ^t Bu) ₄ (350 mg, 0.5 mmol, 1 eq) and 7 mL DMF. The reaction mixture was cooled to 0 °C and DIPEA (348 µL, 258 mg, 2 mmol, 4 eq) was added followed by HBTU (208 mg, 0.55 mmol, 1.1 eq) and stirred at 0 °C for 10 min. The solution was allowed to warm to room temperature and stirred for 15 min and then L-glutamine 5-(tert-butyl) 1-methyl ester HCl (127 mg, 0.5 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. After 2 h, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product, which was purified by RP chromatography to provide intermediate 9-A as a white solid as TFA salt (412 mg, 71%, purity: 97%). An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.67 min; MS (positive ESI): found m/z 900.4 [M+H] ⁺ ; C ₄₅ H ₈₂ N ₅ O ₁₃ (Calculated value 900.6). ₄₅ H ₈₂ N ₅ O ₁₃ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 900.5904; measured value: 900.5936. ¹ H NMR (700 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.05 (s, 1H), 4.35 (s, 1H), 4.24 - 4.19 (m, 1H), 3.62 (s, 3H), 3.28 (s, 3H), 3.07 (s, 2H), 2.58 - 2.51 (m, 1H), 2.45 (s, 1H), 2.25 (t, J = 7.6 Hz, 2H), 1.94 - 1.86 (m, 1H), 1.82 - 1.74 (m, 1H), 1.52 - 1.40 (m, 36H), 1.39 (s, 9H). *Not reported by H ₂ O and DMSO shielded protons. Step 2: Synthesis of (S)-5-(tert-butoxy)-2-((R)-5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-5-oxopentanoic acid (Intermediate 9-B) A mixture containing ((R)-5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-L-glutamine 5-(tert-butyl) 1-methyl ester (Intermediate 9-A) (164 mg, 0.18 mmol, 1 eq.) in a flask was dissolved in THF (5 mL) and water (2.5 mL) and placed in an ice bath and stirred for 10 min. Anhydrous lithium hydroxide (LiOH) (21.8 mg, 0.91 mmol, 5 eq.) was added all at once as a solid and the reaction was stirred in an ice-water bath. The reaction was monitored by HPLC-MS and worked up after 1 h by acidification with Amberlite IR120 [H] to pH ~5 at room temperature and then filtered through a 0.2 µM filter disk to remove the resin. The resin was further washed with ACN, MeOH and the solvent was evaporated under vacuum. The crude product was dissolved in acetonitrile/water and freeze-dried to give intermediate 9-B (159 mg, 94%, purity: 95%) as a white solid. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.57 min; MS (positive ESI): found m/z 886.3 [M+H] ⁺ ; C ₄₄ H ₈₀ N ₅ O ₁₃ (Calculated 886.6). Step 3: Synthesis of (9H-fluoren-9-yl)methyl (2-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)carbamate (Intermediate 9-C) To a 20 mL flash bottle with a stir bar was added (((9H-fluoren-9-yl)methoxy)carbonyl)glycine (24.4 mg, 0.08 mmol, 1 eq) and DMF (1.5 mL). The reaction mixture was cooled to 0 °C and DIPEA (28 µL, 0.16 mmol, 2 eq) was added followed by HBTU (31.4 mg, 0.08 mmol, 1 eq) and stirred at 0 °C for 5 min. The solution was allowed to warm to room temperature and stirred for 20 min and then a solution of intermediate 2-B (55 mg, 0.08 mmol, 1 eq) in DMF (1.5 mL) containing DIPEA (53 µL, 0.24 mmol, 3 eq) was added. The reaction was stirred at room temperature and monitored by HPLC-MS. After 1 h 30 min the reaction was stopped and the solvent was evaporated under vacuum to give a crude product which was purified by normal phase chromatography to provide intermediate 9-C (58 mg, 76%, purity: 98%) as a white solid. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 3.48 min; MS (positive ESI): found m/z 923.1 [M+H] ⁺ ; C ₅₇ H ₅₉ N ₆ O ₆ (Calculated value 923.5). ₅₇ H ₅₉ N ₆ O ₆ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 923.4491. Measured value: 923.4525. ¹ H NMR (700 MHz, DMSO-d6) δ 8.97 (t, J = 5.9 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 7.5 Hz, 2H), 7.44 - 7.30 (m, 13H), 7.25 (d, J = 7.4 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 7.05 (s, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 5.08 (s, 2H), 4.94 (s, 2H), 4.33 - 4.21 (m, 4H), 3.83 (qd, J = 16.7, 5.9 Hz, 2H), 3.78 - 3.72 (m, 1H), 3.66 - 3.59 (m, 1H), 3.18 (q, J = 6.9 Hz, 2H), 3.13 - 3.08 (m, 1H), 2.92 - 2.86 (m, 1H), 2.69 (s, 1H), 2.49 - 2.47 (m, 1H), 1.77 - 1.69 (m, 1H), 1.52 (dd, J = 22.9, 13.0 Hz, 2H), 1.27 - 1.25 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 6H). Step 4: Synthesis of 5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-N-ethyl-4-(4-((1-glyaminopiperidin-4-yl)methyl)phenyl)-4H-1,2,4-triazole-3-carboxamide (Intermediate 9-D) Piperidine (0.45 mL) was added to (9H-fluoren-9-yl)methyl (2-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarboxyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)carbamate (Intermediate 9-C) (50 mg, 0.05 mmol, 1 eq) in DMF (2.55 mL). The reaction was monitored by HPLC-MS and stopped after 1 h at room temperature. The solvent was evaporated under vacuum and the crude product was purified by RP chromatography to yield intermediate 9-D (24.6 mg, 64%, purity 98%) as a white solid. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.48 min; MS (positive ESI): found m/z 701.1 [M+H] ⁺ ; C ₄₂ H ₄₉ N ₆ O ₄ (Calculated value 701.4). Step 5: Synthesis of tert-butyl 2,2',2''-(10-((R)-5-(((S)-1-((2-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)amino)-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 9-E) To a 20 mL flash bottle with a stir bar was added Intermediate 9-B (22.8 [0136] The reaction mixture was cooled to 0 °C and DIPEA (19 µL, 14.2 mg, 0.11 mmol, 4.5 eq.) was added followed by HBTU (9.4 mg, 0.02 mmol, 1 eq.) and stirred at 0 °C for 15 min. The solution was allowed to warm to room temperature and stirred for 20 min and then intermediate 9-D (18 mg, 0.02 mmol, 1 eq.) dissolved in DMF (1 mL) was added. The reaction was stirred at room temperature and monitored by HPLC-MS. After 1 h 45 min, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product, which was purified by RP chromatography to provide intermediate 9-E (30 mg, 65%, purity: 95%) as a white solid as a TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 3.12 min; MS (positive ESI): found m/z 1569.5 [M+H] ⁺ ; C ₈₆ H ₁₂₆ N ₁₁ O ₁₆ (Calculated value 1568.9). ₈₆ H ₁₂₆ N ₁₁ O ₁₆ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1568.9379; measured value: 1568.9403. ¹ H NMR (700 MHz, DMSO-d6) δ 8.98 (td, J = 6.0, 2.2 Hz, 1H), 7.92 (s, 1H), 7.41 - 7.36 (m, 4H), 7.36 (t, J = 7.4 Hz, 2H), 7.35 - 7.29 (m, 2H), 7.27 - 7.23 (m, 2H), 7.10 - 7.06 (m, 2H), 7.03 (d, J = 2.4 Hz, 1H), 7.01 - 6.97 (m, 2H), 6.77 (s, 1H), 5.08 (s, 2H), 4.95 (d, J = 3.3 Hz, 2H), 4.31 - 4.29 (m, 3H), 1.47 - 1.41 (m, 36H), 1.38 (s, 9H), 1.05 (t, J = 7.2 Hz, 3H), 1.04 (dd, J = 6.9, 2.0 Hz, 6H). *Not reported by H ₂ O and DMSO shielded protons. Step 6: Synthesis of tert-butyl 2,2',2''-(10-((R)-1-(tert-butoxy)-5-(((S)-5-(tert-butoxy)-1-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)amino)-1,5-dioxopentan-2-yl)amino)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 9-F) A mixture containing Intermediate 9-E (26 mg, 16.6 µmol, 1 eq.) and methanol (5 To a flask containing 20% 4-nitropropene (2-nitropropene) (4-nitropropene) (5-nitropropene) (6-nitropropene) was added 10% Pd/C (3.4 mg, 3.32 µmol, 0.2 equiv). The reaction mixture was degassed under vacuum and subjected to hydrogen via a balloon. The reaction was stirred overnight and monitored by HPLC-MS. The reaction was stopped after 15 h, filtered through a 0.2 µM filter disk and the solvent evaporated under vacuum to yield the crude intermediate 9-F (22 mg, 86%, purity: 90%) as a colorless film, which was used in the next step without further purification. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.73 min; MS (positive ESI): found m/z 1389.4 [M+H] ⁺ ; C ₇₂ H ₁₁₄ N ₁₁ O ₁₈ (Calculated value 1388.8). Step 7: Synthesis of 2,2',2''-(10-((R)-1-carboxy-4-(((S)-4-carboxy-1-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxobutyl-2-yl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound I) To a 20 mL flash bottle with a stir bar at room temperature was added intermediate 9-F (22 mg, 15.68 µmol) and 2.5 mL of the deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5 (v/v/v). The reaction was warmed to 37 °C by placing on a preheated oil bath at 37 °C and monitored by HPLC-MS. The reaction was stopped after 4 h and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative RP HPLC to provide Compound I as a white solid as TFA salt (5 mg, 23%, purity: 97%). An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 2.84 min; MS (positive ESI): found m/z 1108.5 [M+H] ⁺ ; C ₅₂ H ₇₄ N ₁₁ O ₁₆ (Calculated value 1108.5). ₅₂ H ₇₄ N ₁₁ O ₁₆ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1108.5310. Measured value: 1108.5332. ¹ H NMR (700 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.79 (s, 1H), 8.95 (td, J = 5.9, 2.4 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.95 - 7.91 (m, 1H), 7.28 - 7.26 (m, 3H), 6.57 (d, J = 1.9 Hz, 1H), 6.35 (s, 1H), 4.34 - 4.28 (m, 2H), 4.04 - 3.84 (m, 1H), 3.77 (d, J = 13.5 Hz, 1H), 3.19 - 3.13 (m, 2H), 3.08 (s, 2H), 2.97 - 2.86 (m, 3H), 2.58 - 2.52 (m, 3H), 2.44 (s, 2H), 2.32 - 2.26 (m, 2H), 1.94 - 1.87 (m, 3H), 1.81 - 1.71 (m, 1H), 1.65 - 1.60 (m, 2H), 1.18 - 1.14 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.81 (d, J = 6.9 Hz, 6H). *Not reported by H ₂ Example 10: Synthesis of 2,2',2''-(10-(2-(((S)-1-(((S)-1-(((S)-5-amino-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminoformyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,5-dioxopentan-2-yl)amino)-4-carboxy-1-oxopentan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound J) Step 1: N ² -((S)-5-(tert-butoxy)-5-oxo-2-((S)-5-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)-2-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetamido)pentanamido)pentanyl)-N- ... ⁵ Synthesis of trityl-L-glutamine (intermediate 10-A) The protected peptide was synthesized by solid phase peptide synthesis (SPPS) on 2-chlorotrityl chloride resin (Chem-Impex, 0.72 mmol/g, 139 mg, 0.1 mmol). Fmoc-Gln(Trt)-OH (305 mg, 0.5 mmol) was dissolved in DMF (4 mL) with potassium iodide (16 mg, 0.1 mmol) and DIPEA (174 µL, 1.0 mmol). The resulting solution was combined with the resin and stirred overnight at room temperature. Fmoc deprotection was performed with 20% piperidine in DMF for 5 and 15 min. Subsequent couplings were performed using 0.3 mmol of protected amino acids (Fmoc-Glu(OtBu)-OH, Fmoc-Arg(Pbf)-OH and DOTA(OtBu) ₃ ) 0.3 mmol HBTU and 0.6 mmol DIPEA for 1 hour. The coupling was monitored by Kaiser detection. After the final coupling, the resin was thoroughly washed with DCM. Self-resin cleavage was carried out with 20% HFIP in DCM (5 mL) for 30 minutes. The resin was drained and washed with DCM (2 mL), and the combined washings were concentrated under an air flow. The obtained protected crude peptide was dissolved in DMSO and purified by preparative RP HPLC. After lyophilization, the purified protected peptide intermediate 10-A (38.5 mg, 25%, purity: 98%) was obtained as a colorless solid. Aliquots were analyzed by HPLC-MS using elution method 4; retention time: 4.98 min; for C ₈₀ H ₁₁₈ N ₁₁ O ₁₇ S [M+H] ⁺ , MS (ESI+) m/z calculated value 1536.8; found value 1536.9. ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.63 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.31 (s, 1H), 7.28 - 7.24 (m, 7H), 7.21 - 7.18 (m, 3H), 7.17 - 7.15 (m, 7H), 6.68 (s, 1H), 6.37 (s, 1H), 4.35 - 4.29 (m, 1H), 4.26 (s, 1H), 4.22 - 4.12 (m, 2H), 4.12 - 4.01 (m, 1H), 3.92 (s, 1H), 3.60 - 3.43 (m, 5H), 3.36 (s, 3H), 9 (m, 2H), 3.85 (m, 4H), 3.70 (s, 3H), 3.79 (m, 2H), 3.85 (m, 2H), 3.10 (m, 1H), 3.73 (m, 2H), 3.91 (m, 3H), 3.89 (s, 2H), 3.85 (m, 1H), 3.13 (m, 3H), 3.25 (m, 2H), 3.30 (m, 3H), 3.33 (m, 2H), 3.36 (m, 2H), 3.54 (m, 1H), 3.55 (m, 2H), 3.72 (m, 2H), 3.84 (m, 1H), 3.85 (m, 3H), 9H), 1.40 (s, 9H), 1.38 (m, 27H). Step 2: 2,2',2''-(10-((6S,9S,12S)-6-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidine-1-carbonyl)-9-(3-(tert-butoxy)-3-oxopropyl)-3,8,11,14-tetrahydroxy Synthesis of tert-butyl-12-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-1,1,1-triphenyl-2,7,10,13-tetraazapentadecan-15-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 10-B) Intermediate 10-A (21 mg, 0.02 mmol), intermediate 2-B (15 mg, 0.022 mmol), HBTU (7.6 mg, 0.02 mmol) and DIPEA (18 µL, 0.1 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was redissolved in DMSO (<1 mL). The crude product was purified by preparative RP HPLC to yield intermediate 10-B (23 mg, 54%, purity: 98%) as a colorless solid after lyophilization. An aliquot was analyzed by HPLC-MS using elution method 4; retention time: 6.15 min; for C ₁₂₀ H ₁₆₂ N ₁₆ O ₁₉ S [M+2H] ²⁺ , MS (ESI+) m/z calculated value 1082.1; found value 1082.3. Step 3: Synthesis of 2,2',2''-(10-(2-(((S)-1-(((S)-1-(((S)-5-amino-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminoformyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,5-dioxopentan-2-yl)amino)-4-carboxy-1-oxopentan-2-yl)amino)-5-guanidino-1-oxopentan-2-yl)amino)-2-oxopentan-2-yl)ethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound J) 10% w/w palladium on carbon (30% w/w, 3.5 mg) was added to a 5 mL microwave vial with a stir bar and sealed with a septum and screw cap. The vial was purged with nitrogen and then intermediate 10-B (23 mg, 10.8 µmol) dissolved in methanol (2 mL) was added. The vial was then purged with hydrogen and a hydrogen balloon attached to the vial. After stirring at room temperature for 2 hours, the vial was purged with nitrogen and the vial was not sealed. The reaction mixture was filtered through a 0.2 µm syringe filter and the solvent was evaporated under reduced pressure. The resulting product was dissolved in 2 mL 95:2.5:2.5 TFA/ /TIPS/H ₂ O (v/v/v) and stirred at 37 °C in a heating block for 90 min. The solvent was then evaporated under a stream of air and the resulting crude product was redissolved in DMSO, filtered through a 0.2 µm syringe filter and purified by preparative RP HPLC. After lyophilization, compound J (5.9 mg, 34%, purity: 99%) was obtained as a colorless solid as TFA salt. An aliquot was analyzed by HPLC-MS using elution method 4; retention time: 4.53 min; for C ₅₈ H ₈₈ N ₁₆ O ₁₆ [M+2H] ²⁺ , HRMS (ESI+) m/z calculated value 632.3277; found value 632.3268. ¹ H NMR (700 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 8.96 (t, J = 5.4 Hz, 1H), 8.71 (s, 1H), 8.27 - 8.03 (m, 2H), 7.81 (s, 1H), 7.29 - 7.25 (m, 4H), 7.25 (m, 1H), 6.82 (m, 1H), 6.57 (s, 1H), 6.36 (s, 1H), 4.79 - 4.67 (m, 2H), 4.43 - 4.32 (m, 4H), 4.32 - 4.28 (m, 1H), 4.27 - 4.22 (m, 1H), 4.12 - 3.88 (m, 9H), 3.71 - 3.52 (m, 9 - 1.57 (m, 3H), 1.65 - 1.84 (m, 3H), 1.23 - 1.69 (m, 4H), 3.47 - 3.24 (m, 7H), 3.19 - 3.15 (m, 2H), 3.13 - 3.02 (m, 8H), 3.02 - 2.93 (m, 1H), 2.90 (h, J = 6.7 Hz, 1H), 2.32 - 2.20 (m, 2H), 2.20 - 2.00 (m, 2H), 1.97 - 1.82 (m, 2H), 1.81 - 1.68 (m, 3H), 1.68 - 1.59 (m, 3H), 1.59 - 1.45 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H), 0.81 (d, J = 6.7 Hz, 6H). *9 exchangeable protons were not observed. Example 11: Synthesis of (S)-2,2',2''-(10-(1-carboxy-4-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-carboxamido)ethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound K) Step 1: 2,2',2''-(10-(5-((2-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-carboxamido)ethyl)amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclopentane Synthesis of tert-butyl)(S)-triacetate (Intermediate 11-A) To a solution of 2,2',2''-(10-(5-((2-aminoethyl)amino)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetate (Intermediate 5-A) (50 mg, 0.06 mmol, 1 eq) in anhydrous THF (4 mL) and a stir bar was added DIPEA (32 µL, 0.18 mmol, 3 eq) and cooled to 0 °C, followed by the addition of 4-nitrophenyl chloroformate (12.7 mg, 0.06 mmol, 1 eq) all at once at 0 °C. The reaction was initially stirred at 0 °C for 20 min, then allowed to warm to room temperature and monitored by HPLC-MS. After 30 min at room temperature, complete conversion to the nitrophenyl intermediate was observed by HPLC-MS. Intermediate 2-B (59 mg, 0.08 mmol, 1.4 eq) was added to the reaction as a solid and stirring continued at room temperature. After 1 h, additional intermediate 2-B (26 mg, 0.04 mmol, 0.6 eq) was added, followed by DIPEA (32 µL, 0.18 mmol, 3 eq). The reaction mixture was warmed to 50 °C and stirring continued overnight. After 16 h at 50 °C, the reaction was stopped by the addition of methanol and stirred for 10 min at room temperature. The reaction mixture was concentrated under vacuum and then subjected to RP chromatography to provide intermediate 11-A as a white solid as a TFA salt (34 mg, 40%, purity: 95%). An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.92 min; MS (positive ESI): found m/z 1412.5 [M+H] ⁺ ; C ₇₈ H ₁₁₄ N ₁₁ O ₁₃ (Calculated value 1412.9). ₇₈ H ₁₁₄ N ₁₁ O ₁₃ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1412.8592. Measured value: 1412.8552. ¹ H NMR (700 MHz, DMSO-d6) δ 8.99 (t, J = 5.9 Hz, 1H), 7.96 (br s, 1H), 7.42 - 7.34 (m, 6H), 7.36 - 7.30 (m, 2H), 7.28 - 7.24 (m, 2H), 7.11 - 7.06 (m, 4H), 7.03 (s, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.78 (s, 1H), 6.51 (t, J = 5.5 Hz, 1H), 5.09 (s, 2H), 4.96 (s, 2H), 4.43 - 3.94 (m, 1H), 3.89 (d, J = 12.8 Hz, 2H), 3.20 - 3.15 (m, 2H), 3.14 - 2.98 (m, 7H), 2.56 (t, J = 12.5 Hz, 2H), 2.48 (d, J = 7.1 Hz, 2H), 1.51 - 1.39 (m, 40H), 1.05 (t, J = 7.2 Hz, 3H), 1.01 (d, J = 6.9 Hz, 6H). * Not reported by H ₂ O and DMSO shielded protons. Step 2: Synthesis of tert-butyl 2,2',2''-(10-(1-(tert-butoxy)-5-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-carboxamido)ethyl)amino)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(S)-triacetate (Intermediate 11-B) To a flask containing intermediate 11-A (30 mg, 19.11 µmol) and methanol (4.5 mL) was added 10% Pd/C (8 mg, 7.64 µmol, 0.4 eq) at room temperature. The reaction mixture was degassed under vacuum and subjected to hydrogen via a balloon. The reaction was stirred overnight and monitored by HPLC-MS. The reaction was stopped after 15 h, filtered through a 0.2 μM filter disk and the solvent evaporated under vacuum to give a crude product, which was purified by RP chromatography to afford intermediate 11-B as a white solid as a TFA salt (18.4 mg, 66%, purity: 98%). An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 4.78 min; MS (positive ESI): found m/z 1232.5 [M+H] ⁺ ; C ₆₄ H ₁₀₂ N ₁₁ O ₁₃ (Calculated value 1232.8). ₆₄ H ₁₀₂ N ₁₁ O ₁₃ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1232.7680. Measured value: 1232.7680. ¹ H NMR (700 MHz, DMSO-d6) δ 9.82 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.31 - 7.25 (m, 4H), 7.11 (s, 2H), 6.57 (s, 1H), 6.54 (br s, 1H), 6.37 (s, 1H), 3.92 (d, J = 13.4 Hz, 2H), 3.20 - 3.13 (m, 2H), 3.10 - 3.01 (m, 8H), 2.94 - 2.87 (m, 1H), 2.61 - 2.54 (m, 4H), 2.47 - 2.39 (m, 2H), 1.72 - 1.65 (m, 1H), 1.57 (d, J = 12.6 Hz, 2H), 1.51 - 1.37 (m, 38H), 1.09 - 1.05 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.0 Hz, 6H). * Not reported by H ₂ O and DMSO-shielded protons. Step 3: Synthesis of (S)-2,2',2''-(10-(1-carboxy-4-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-carboxamido)ethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound K) To a 20 mL flash bottle with a stir bar at room temperature was added intermediate 11-B (18 mg, 10.73 µmol, 1 eq) and 2.5 mL of the deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5 (v/v/v). The reaction was warmed to 37 °C by placing on a preheated oil bath at 37 °C and monitored by HPLC-MS. The reaction was stopped after 4 h and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative RP HPLC to provide compound K as a white solid as TFA salt (13 mg, 97%, purity: 99%). An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 2.89 min; MS (positive ESI): found m/z 1009.0 [M+H] ⁺ ; C ₄₈ H ₇₀ N ₁₁ O ₁₃ (Calculated value 1008.5). ₄₈ H ₇₀ N ₁₁ O ₁₃ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1008.5149; measured value: 1008.5157. ¹ H NMR (700 MHz, DMSO-d6) δ 13.14 (br s, 2H), 10.71 (br s, 1H), 9.84 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 7.93 (br s, 1H), 7.29 - 7.24 (m, 4H), 6.58 (s, 1H), 6.57 (s, 1H), 6.36 (s, 1H), 3.92 (d, J = 12.9 Hz, 2H), 3.29 - 3.20 (m, 1H), 3.19 - 3.13 (m, 2H), 3.07 (d, J = 5.6 Hz, 6H), 2.93 - 2.87 (m, 1H), 2.61 - 2.53 (m, 4H), 2.42 - 2.33 (m, 3H), 2.00 - 1.83 (m, 2H), 1.71 - 1.64 (m, 1H), 1.56 (app. dd, J = 13.3, 3.6 Hz, 2H), 1.09 - 1.05 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.8 Hz, 6H). *Not reported by H ₂ O and DMSO shielded protons. Example 12: Synthesis of 2,2',2''-(10-((R)-1-carboxy-4-(((S)-4-carboxy-1-((2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminoformyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxobutyl-2-yl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound L) Step 1: Synthesis of tert-butyl 2,2',2''-(10-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (Intermediate 12-A) To a 20 mL flash bottle with a stir bar was added 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid, DOTA-tris( ^t Bu) ester (20.2 mg, 0.04 mmol, 1 eq) and DMF (2 mL). The reaction mixture was cooled to 0 °C and DIPEA (25 µL, 18.2 mg, 0.14 mmol, 4 eq) was added followed by HBTU (13.6 mg, 0.04 mmol, 1 eq) and stirred at 0 °C for 10 min. The solution was allowed to warm to room temperature and stirred for 15 min and then intermediate 1-C (18 mg, 0.04 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. The reaction was stopped after 4 h and the solvent was evaporated under vacuum to give a crude product, which was purified by RP chromatography to provide intermediate 12-A (38 mg, 73%, purity: 85%) as a white solid as a TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.44 min; MS (positive ESI): found m/z 1018.0 [M+H] ⁺ ; C ₅₄ H ₈₄ N ₉ O ₁₀ (Calculated value 1018.6). For C ₅₄ H ₈₄ N ₉ O ₁₀ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1018.6336. Measured value: 1018.6345. ¹ H NMR (700 MHz, DMSO-d6) δ 9.88 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.34 (br s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.55 (s, 1H), 6.37 (s, 1H), 4.32 (d, J = 12.8 Hz, 1H), 4.13 (br s, 5H), 3.67 - 3.62 (m, 2H), 3.16 (p, J = 6.9 Hz, 2H), 3.08 - 3.00 (m, 1H), 2.98 - 2.86 (m, 3H), 2.65 - 2.53 (m, 3H), 1.86 - 1.78 (m, 1H), 1.70 (d, J = 12.6 Hz, 1H), 1.62 (d, J = 12.6 Hz, 1H), 1.52 - 1.35 (m, 32H), 1.23 (t, J = 10.4 Hz, 1H), 1.06 (d, J = 10.4 Hz, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.78 (dd, J = 7.0, 3.2 Hz, 6H). Not reported for H ₂ O and DMSO shielded protons. Step 2: Synthesis of 2,2',2''-(10-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound L) To a 20 mL flash bottle with a stir bar at room temperature was added intermediate 12-A (25 mg, 21 µmol) and 2.5 mL of the deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5 (v/v/v). The reaction was warmed to 37 °C by placing on a preheated oil bath at 37 °C and monitored by HPLC-MS. The reaction was stopped after 2 h 30 min and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative RP HPLC to provide Compound L (11 mg, 48%, purity: 99%) as a white solid as TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 2.78 min; MS (positive ESI): found m/z 850.0 [M+H] ⁺ ; C ₄₂ H ₆₀ N ₉ O ₁₀ (Calculated value 850.4). ₄₂ H ₆₀ N ₉ O ₁₀ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 850.4458. Measured value: 850.4456. ¹ H NMR (700 MHz, DMSO-d6) δ 12.95 (br s, 2H), 9.85 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.77 (br s, 1H), 7.31 - 7.25 (m, 4H), 6.57 (s, 1H), 6.36 (s, 1H), 4.39 - 4.01 (m, 6H), 3.59 (d, J = 13.3 Hz, 1H), 3.39 (br s, 8H), 3.19 - 3.13 (m, 2H), 3.09 (d, J = 17.5 Hz, 2H), 2.99 - 2.87 (m, 2H), 2.68 - 2.55 (m, 3H), 1.85 - 1.79 (m, 1H), 1.68 - 1.63 (m, 2H), 1.28 - 1.21 (m, 1H), 1.16 - 1.09 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H), 0.81 (d, J = 6.9 Hz, 6H). * Not reported by H ₂ Example 13: Synthesis of (R)-2,2',2''-(10-(1-carboxy-4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound M) Step 1: Synthesis of 2,2',2''-(10-(1-(tert-butoxy)-5-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-tert-butyl triacetate (Intermediate 13-A) To a 20 mL flash bottle with a stir bar was added (R)-DOTAGA ( ^t Bu) ₄ (15 mg, 0.02 mmol, 1 eq) was added followed by THF (0.9 mL) and DMF (0.1 mL). The reaction mixture was cooled to 0 °C and DIPEA (11.3 µL, 8.4 mg, 0.06 mmol, 3 eq) and HBTU (11 mg, 0.03 mmol, 1.3 eq) were added and stirred at 0 °C for 10 min. The solution was allowed to warm to room temperature and stirred for 15 min and then intermediate 1-C (12 mg, 0.02 mmol, 1 eq) was added as a solution in THF (0.4 mL) and DMF (0.3 mL) along with 5 µL DIPEA. The reaction was stirred at room temperature and monitored by HPLC-MS. After 2 h, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product, which was purified by RP chromatography to afford intermediate 13-A (8.6 mg, 33%, purity: 96%) as a white solid as a TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 2; retention time: 2.64 min; MS (positive ESI): found m/z 1146.5 [M+H] ⁺ ; C ₆₁ H ₉₆ N ₉ O ₁₂ (Calculated value 1146.7). ₆₁ H ₉₆ N ₉ O ₁₂ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1146.7173. Measured value: 1146.7145. ¹ H NMR (700 MHz, DMSO-d6) δ 10.67 (br s, 2H), 9.80 (br s, 1H), 8.96 (t, J = 6.5 Hz, 1H), 7.31 - 7.23 (m, 5H), 6.56 (d, J = 4.0 Hz, 1H), 6.36 (d, J = 2.3 Hz, 1H), 4.36 (s, 3H), 3.90 - 3.78 (m, 4H), 3.72 (br s, 2H), 3.18 - 3.13 (m, 3H), 3.06 (br s, 5H), 2.94 - 2.86 (m, 4H), 2.77 (br s, 3H), 2.58 - 2.54 (m, 2H), 1.96 - 1.87 (m, 2H), 1.84 - 1.73 (m, 3H), 1.68 - 1.59 (m, 3H), 1.51 - 1.37 (m, 38H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (app. dd, J = 6.9, 2.7 Hz, 6H). *Not reported by H ₂ O and DMSO-shielded protons. Step 2: Synthesis of (R)-2,2',2''-(10-(1-carboxy-4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound M) To a 20 mL flash vial with a stir bar at 0 °C was added intermediate 13-A (7 mg, 0.01 µmol) and 0.6 mL of the deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5 (v/v/v). After 5 min, the reaction was allowed to warm to room temperature and monitored by HPLC-MS. After 18 h, the reaction was stopped and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative RP HPLC to provide Compound M (4.3 mg, 79%, purity: 99%) as a white solid as a TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 2.83 min; MS (positive ESI): found m/z 922.2 [M+H] ⁺ ; C ₄₅ H ₆₄ N ₉ O ₁₂ (Calculated value 922.5). ₄₅ H ₆₂ N ₉ O ₁₂ , HRMS (ESI-TOF) m/z: [M - H] ^- Calculated value: 920.4523; measured value: 920.4518. ¹ H NMR (700 MHz, DMSO-d6) δ 9.80 (br s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.27 (d, J = 4.1 Hz, 4H), 6.57 (s, 1H), 6.35 (s, 1H), 4.36 (t, J = 14.6 Hz, 2H), 3.89 - 3.77 (m, 5H), 3.19 - 3.13 (m, 5H), 3.07 (s, 1H), 2.98 - 2.87 (m, 6H), 2.63 - 2.52 (m, 5H), 1.92 (s, 1H), 1.81 - 1.75 (m, 2H), 1.66 (d, J = 12.6 Hz, 1H), 1.61 (d, J = 12.6 Hz, 1H), 1.15 - 1.12 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.02 - 0.97 (m, 2H), 0.81 (d, J = 6.8 Hz, 6H). * Not reported by H ₂ Example 14: Synthesis of (R)-2,2',2''-(10-(4-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound N) Step 1: Synthesis of 2,2',2''-(10-(5-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1-(tert-butoxy)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(R)-triacetic acid tert-butyl ester (Intermediate 14-A) To a 20 mL flash bottle with a stir bar was added (R)-DOTAGA( ^t Bu) ₄ (24.5 mg, 0.03 mmol, 1 eq) and 2 mL DMF. The reaction mixture was cooled to 0 °C and DIPEA (30.3 µL, 22.5 mg, 0.17 mmol, 5 eq) was added followed by HBTU (13.5 mg, 0.03 mmol, 1 eq) and stirred at 0 °C for 15 min. The solution was allowed to warm to room temperature and stirred for 15 min and then intermediate 2-B (23 mg, 0.03 mmol, 1 eq) was added as a solid. The reaction was stirred at room temperature and monitored by HPLC-MS. After 16 h, the reaction was stopped and the solvent was evaporated under vacuum to give a crude product, which was purified by RP chromatography to provide intermediate 14-A (47 mg, 83%, purity: 95%) as a white solid as a TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 6.31 min; MS (positive ESI): found m/z 1327.0 [M+H] ⁺ ; C ₇₅ H ₁₀₈ N ₉ O ₁₂ (Calculated value 1326.8). ₇₅ H ₁₀₈ N ₉ O ₁₂ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1326.8112. Measured value: 1326.8142. ¹ H NMR (700 MHz, DMSO-d6) δ 8.98 (td, J = 6.1, 2.6 Hz, 1H), 7.41 - 7.38 (m, 4H), 7.38 - 7.30 (m, 5H), 7.28 - 7.24 (m, 2H), 7.08 (dd, J = 15.5, 8.0 Hz, 2H), 7.04 - 6.98 (m, 3H), 6.78 (s, 1H), 5.08 (s, 2H), 4.97 (s, 2H), 4.34 - 4.30 (m, 1H), 3.91 - 3.65 (m, 3H), 3.28 (br s, 1H), 3.20 - 3.15 (m, 2H), 3.14 - 3.00 (m, 2H), 2.94 - 2.85 (m, 1H), 2.79 - 2.63 (m, 2H), 2.49 - 2.41 (m, 2H), 1.77 - 1.70 (m, 1H), 1.60 - 1.51 (m, 2H), 1.47 (br s, 11H), 1.43 - 1.34 (m, 25H), 1.05 (t, J = 7.2 Hz, 3H), 1.02 - 0.99 (m, 6H), 0.97 - 0.90 (m, 1H). * Not reported by H ₂ O and DMSO masked protons. Step 2: Synthesis of (R)-2,2',2''-(10-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(ethylaminocarbonyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (Compound N) To a 20 mL flash bottle with a stir bar at room temperature was added intermediate 14-A (25 mg, 18.65 µmol, 1 eq) and 2.5 mL of the deprotection mixture TFA:TIPS:H ₂ O - 95:2.5:2.5 (v/v/v). The reaction was warmed to 37 °C by placing on a preheated oil bath at 37 °C and monitored by HPLC-MS. The reaction was stopped after 2 h 30 min and the reaction mixture was placed under a stream of air to remove TFA. The crude product was purified by preparative RP HPLC to provide Compound N (15 mg, 60%, purity: 99%) as a white solid as TFA salt. An aliquot was analyzed by HPLC-MS elution using elution method 1; retention time: 4.37 min; MS (positive ESI): found m/z 1102.2 [M+H] ⁺ ; C ₅₉ H ₇₆ N ₉ O ₁₂ (Calculated value 1102.6). For C ₅₉ H ₇₆ N ₉ O ₁₂ , HRMS (ESI-TOF) m/z: [M + H] ⁺ Calculated value: 1102.5608. Measured value: 1102.5624. ¹ H NMR (700 MHz, DMSO-d6) δ 13.16 (br s, 2H), 8.98 (t, J = 5.9 Hz, 1H), 7.40 - 7.38 (m, 4H), 7.37 - 7.30 (m, 4H), 7.25 (dd, J = 7.0, 1.7 Hz, 2H), 7.09 (dd, J = 8.5, 2.5 Hz, 2H), 7.03 (d, J = 1.6 Hz, 1H), 6.99 (dd, J = 8.4, 2.3 Hz, 2H), 6.77 (s, 1H), 5.08 (s, 2H), 4.95 (app. d, J = 2.9 Hz, 2H), 4.41 - 4.26 3.90 - 3.85 (m, 15H), 3.79 (t, J = 15.0 Hz, 1H), 3.56 - 3.24 (m, 5H), 3.21 - 3.14 (m, 2H), 3.14 - 3.06 (m, 1H), 2.96 - 2.86 (m, 2H), 2.62 - 2.54 (m, 1H), 2.50 - 2.41 (m, 2H), 1.99 - 1.84 (m, 1H), 1.77 - 1.69 (m, 1H), 1.58 (d, J = 12.3 Hz, 1H), 1.52 - 1.49 (m, 1H), 1.11 - 1.07 (m, 1H), 1.05 (t, J = 7.2 Hz, 3H), 1.01 (d, J = 6.9 Hz, 6H), 0.98 - 0.90 (m, 1H). *Not reported by H ₂ O and DMSO-shielded protons. Example 15: Method for radiolabeling compounds disclosed herein Prior to radiolabeling, a stock solution of each compound is prepared by dissolving an appropriate amount of the compound in sodium acetate buffer. Up to 10% by volume of ethanol may be added to improve the solubility of the compounds. A 1.5 mL Eppendorf tube is charged with the desired compound followed by sodium acetate buffer to increase the total volume as needed (0.05 to 0.5 mL). Next, [177Lu]LuCl is added ₃ or [111In]InCl ₃ or [225Ac]AcNO ₃ (or [225Ac]AcCl ₃ ) in hydrochloric acid solution and heating the mixture. After the reaction is heated for the desired amount of time, iTLC analysis of the reaction mixture (solid phase: silica gel (SG) or silicic acid (SA) disks; mobile phase: 0.02 M citrate buffer with 5% MeOH) indicates acceptable radiochemical conversion (RCC), typically >95%. To the reaction mixture are added sodium L-ascorbate and diethylenetriamine-pentaacetic acid calcium trisodium salt hydrate (DTPA) in sodium acetate buffer. iTLC and reverse phase HPLC (elution method 5) at the end of synthesis (EOS) indicate the formation of the desired radiolabeled product with typically >95% radiochemical purity (RCP). Table 1: Radiochemical analysis of the reaction mixture using [177Lu]LuCl ₃ Radiolabeled compounds. Compound RCP of 177Lu-compounds during EOS Compound A >99% Compound B 99% Compound C 95% Compound D >99% Compound E >99% Compound F >99% Compound G >99% Compound H >99% Compound I >99% Compound J 98% Compound K >99% Compound L >99% Compound M >99% Compound N >99% Table 2: [111In]InCl ₃ Radiolabeled compounds. Compound RCP of 111In-compounds during EOS Compound A >99% Compound B 97% Compound C 90% Compound D >99% Compound G >99% Compound M >99% Table 3: Radiolabeling of compounds with [225Ac]. Compound RCP of 225Ac-compounds during EOS Compound A 98% Compound D >99% Compound G >99% The following shows [177Lu]LuCl ₃ 、[111In]InCl ₃ or [225Ac] radiolabeled samples of compounds characterizing DOTAGA chelators. The following shows [177Lu]LuCl ₃ 、[111In]InCl ₃ , or [225Ac] radiolabeled samples of compounds characterizing DOTA chelators. Example 16: In vitro HSP90 binding studies of radiopharmaceuticals comprising compounds of Formula I HSP90 binding was determined using a cell-free binding affinity assay in which recombinant HSP90 protein was coated onto Reacti-Bind® microtiter plates. Plates were incubated overnight at 4°C and then washed three times with cold PBS containing 0.05% Tween-20 (PBS-T). Plates were equilibrated to room temperature, blocked on ice for 1 hour with PBS-T containing 0.2% gelatin, and then washed three times with PBS-T. Increasing concentrations of radiolabeled (Lu-177) conjugate were incubated in the absence or presence of unlabeled conjugate and incubated at 37°C for 1 hour with gentle shaking. The wells were then rinsed three times with PBS-T and stripped with a solution of 20 mM sodium acetate, pH 3.0 at room temperature for 20 min, followed by neutralization with an equal volume of 0.1 N NaOH solution. The samples were transferred to gamma counter tubes and analyzed for Lu-177 content by gamma counter. The results were plotted against the molar concentration of the labeled conjugate, where the specific binding affinity (K) was calculated using Graph Pad Prism. _d ). Binding affinity (K _d ) The results are summarized in Table 4, where 0 nM < A ≤ 5 nM, 5 nM < B ≤ 100 nM, and C > 100 nM. Table 4: Binding affinity (K) of selected compounds to recombinant Hsp90α or β isoforms _d ). Compound K _d (nM) Hsp90α Hsp90β Compound A A A Compound B A A Compound C A A Compound D A A Compound E A A Compound F A A Compound G A A Compound H A A Compound I A B Compound J A A Compound K A A Compound L A A Compound M A A Compound N C C Example 17: Biodistribution studies of radiopharmaceuticals comprising compounds of Formula I In an animal model, the accumulation of indium-177 (Lu-177) or indium (In-111) was measured in tumors, blood, and healthy tissues of mice bearing subcutaneous xenograft tumors. Tumor-bearing mice were dosed with 20 μCi of Lu-177 or In-111 conjugates. At the indicated time points (1 h, 4 h, 24 h), mice were sacrificed, and tumors, livers, kidneys, and blood were isolated. The content of Lu-177 or In-111 in all tissues was analyzed by a gamma counter, and radioligand uptake was determined as a percentage of injected dose per gram of tissue (%ID/g). Mean radioligand uptake (%ID/g, n = 3) is summarized in Table 5. Table 5. Biodistribution of selected compounds in tumor-bearing mice. Compound Lu-177 or In-111 Biodistribution (%ID/g) 1 h 4 h 24h Tumor blood liver Kidney Tumor blood liver Kidney Tumor blood liver Kidney Compound A 14.60 13.93 5.01 6.47 20.85 6.70 6.44 8.47 14.98 0.52 2.81 5.55 Compound B 12.97 15.33 7.38 7.28 10.41 7.80 7.25 6.34 5.59 0.37 1.38 0.87 Compound C 7.37 17.08 4.50 7.50 11.51 11.95 5.48 7.83 5.74 0.84 2.19 2.31 Compound D 9.22 16.35 7.43 9.41 13.01 9.40 7.69 10.91 10.19 0.48 3.43 6.06 Compound G 6.74 10.45 17.19 8.00 5.71 5.25 18.43 7.56 6.37 0.25 5.82 5.68 Compound I 16.19 10.09 10.47 8.31 16.46 3.40 10.08 8.87 10.15 0.20 3.16 6.05 Compound L 4.82 7.68 32.84 5.35 5.42 0.73 39.74 3.65 3.25 0.18 10.38 2.57 Example 18: In vivo studies of radiopharmaceuticals comprising compounds of Formula I The in vivo efficacy of compounds of Formula I was determined by evaluating overall survival and tumor growth regression in mice bearing xenograft tumors expressing HSP90 using an in vivo model. Mice implanted with xenograft tumors expressing HSP90 were treated with compounds of Formula I at varying concentrations and doses to evaluate in vivo efficacy. To determine the most effective dose range, a preclinical dose escalation study was performed. The average tumor growth inhibition in response to increasing doses of 225Ac-Compound D compared to vehicle (buffer control) and non-radiolabeled Compound D is presented in Figure 1 (n = 5 animals/group). It was observed that 225Ac-Compound D administered at 3 μCi was effective in significantly inhibiting tumor growth. Other Examples

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the scope of the appended claims.

Figure 1. Tumor growth of xenograft tumors expressing HSP90 in response to treatment with 225Ac-Compound D.

Claims (22)

A compound of formula I or a pharmaceutically acceptable salt thereof, (I), wherein X is absent, C=O or (C=O)NR ¹ , R ¹ is H, alkyl, aryl, (C-CF ₃ )R ² or (SO ₂ )R ² , R ² is alkyl or aryl; Y is independently O or NR ³ , R ³ is H, alkyl, aryl or acyl; n is an integer from 0 to 5 (inclusive); Z ¹ and Z ² are independently absent, an amino acid unit, (C=O)NR ⁴ (CH ₂ CH ₂ )O or (C=O)NR ⁴ (CH ₂ CH ₂ )NR ⁵ , wherein R ⁴ and R ⁵ are independently H or alkyl or (C-CF ₃ )R ⁶ or (SO ₂ )R ⁶ , R ⁶ is alkyl or aryl; and W is a chelating agent selected from the group consisting of DOTA, DOTAGA, NOTA and NODAGA, wherein when W is DOTA, at least one of ^Z1 and ^Z2 is an amino acid unit, or ^Z1 and ^Z2 are each absent, and n is equal to or less than 4, wherein the compound binds to HSP90, wherein the compound further comprises a radionuclide chelated by a chelator thereof as necessary. The compound of claim 1 has a structure of formula II: (II), wherein X, Y, n, ^Z1 and ^Z2 are each as defined in claim 1. The compound of claim 1 or 2, wherein at least one of Z ¹ and Z ² is an amino acid unit. A compound as claimed in any one of claims 1 to 3, wherein the amino acid unit is formed by: glycine (Gly), aspartic acid (Asp), glutamine (Glu), 2,4-diaminobutyric acid (Dab), 2,3-diaminopropionic acid (Dap), lysine (Lys), arginine (Arg), or a combination thereof. The compound of any one of claims 1 to 4, wherein the amino acid unit comprises an organic moiety formed of Asp. The compound of claim 1 or 2, wherein X is C=O. The compound of claim 1 or 2, wherein n is 4 or 5. The compound of claim 1 or 2, wherein Z ¹ and Z ² are each absent. The compound of claim 1 or 2, wherein X is absent, n is 0, Z ¹ is absent, and Z ² is an amino acid unit. The compound of claim 1 or 2, wherein X is C=O, n is 4 or 5, Z ¹ is an amino acid unit, and Z ² is absent. The compound of claim 1 or 2, wherein X is C=O, n is 4 or 5, Z ¹ is absent, and Z ² is an amino acid unit. The compound of claim 1 or 2, wherein X is (C=O)NH, n is 4 or 5, and ^Z1 and ^Z2 are each absent. The compound of claim 1 or 2, wherein X is C=O, n is 4 or 5, Z ¹ is absent, and Z ² is (C=O)NH(CH ₂ CH ₂ )NH. The compound of claim 1 or 2, wherein X is absent, n is 0, and ^Z1 and ^Z2 are each absent. The compound of claim 1 or 2, wherein the compound is one of the following: , , , , , , , , , , , and . 17m Sn, 182 La, ¹⁸³ Ce, ¹⁸⁴ Pm, 185 Tb, 186 Ho, 187 Lu, ¹⁹¹ Re, 192 ^Pd , ¹⁹³ In ^, 194 ^Sn, 195 La, ¹⁹⁶ Ce, ¹⁹⁷ Pm, ²⁰⁰ Sm, 201 Tb ^{, 202} Tb ^{, 203} Sm ^, 204 Ho, ^{205 Rb, 206 Y} , ²⁰⁷ Y, ²⁰⁸ Re, ²⁰⁹ Rh, ²¹⁰ In, ^{211 M} Sn, ^{212 La} , ²¹³ Ce, ²¹⁴ Pm, ²¹⁵ Tb ^{, 216 Ho, 217 Lu, 218 Re , 220 Mn , 221 Mn} , ^{222 Mn 199} Au, ²⁰¹ Tl, ²⁰³ Pb, ²¹¹ At, ²¹² Pb, ²¹² Bi, ²¹³ Bi, ²²³ Ra, ²²⁵ Ac, ²²⁷ Th and ²²⁹ Th. The compound of claim 16, wherein the radionuclide is selected from the group consisting of ⁶⁸ Ga, ⁸⁹ Zr, ⁹⁰ Y, ¹¹¹ In, ¹⁷⁷ Lu and ²²⁵ Ac. The compound of claim 17, wherein the radionuclide is ¹⁷⁷ Lu or ²²⁵ Ac. The compound of any one of claims 1 to 18, wherein the compound binds to extracellular HSP90 (eHSP90). A pharmaceutical composition comprising the compound of any one of claims 1 to 19 and a pharmaceutically acceptable excipient. A method for treating cancer, wherein the method comprises administering a therapeutically effective amount of a compound of any one of claims 1 to 19 or a composition of claim 20 to a subject in need thereof. The method of claim 21, wherein the cancer is small cell lung cancer, non-small cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.