Folate receptor targeted radiotherapeutic agents and their uses

Abstract

The present disclosure relates to folate receptor targeted radiotherapeutic compounds and their uses.The present disclosure relates to folate receptor targeted radiolabeled diagnostic imaging conjugates and their uses.The present disclosure also relates to pharmaceutical compositions of the compounds and conjugates described herein, methods of making them, and methods of using them.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Patent Application No. 63 / 175,883, filed April 16, 2021, which is incorporated herein by reference in its entirety and for all purposes.

[0002] The present disclosure relates to folate receptor-targeted radiotherapeutic compounds and their uses, for example, in radionuclide therapy, diagnostic imaging, diagnostic, and therapeutic diagnostic methods. The present disclosure also relates to pharmaceutical compositions of the compounds described herein, methods of making the same, and methods of using the same. [Background technology]

[0003] The mammalian immune system provides a means for the recognition and elimination of pathogenic cells, such as tumor cells, and other invading foreign pathogens. While the immune system typically provides a strong line of defense, there are many examples in which pathogenic cells, such as cancer cells, and other infectious pathogens, evade the host immune response and proliferate or persist, resulting in host pathogenicity. Chemotherapeutic agents and radiation therapy have been developed, for example, to eliminate replicating neoplasms. However, many currently available chemotherapeutic and radiation therapy regimens have harmful side effects because they are not sufficiently selective to preferentially destroy pathogenic cells and therefore may also harm normal host cells, such as cells of the hematopoietic system, and other non-pathogenic cells. The harmful side effects of these anti-cancer drugs highlight the need for the development of new therapies that are selective for pathogenic cell populations and have reduced host toxicity.

[0004] Researchers have developed therapeutic protocols for destroying pathogenic cells by targeting cytotoxic compounds to such cells. Many of these protocols utilize toxins conjugated to antibodies that bind to antigens unique to or overexpressed by pathogenic cells, to minimize delivery of the toxin to normal cells. Using this approach, certain immunotoxins have been developed, consisting of antibodies directed against specific antigens on pathogenic cells, which are linked to toxins such as ricin, Pseudomonas toxin, Diptheria toxin, and tumor necrosis factor. These immunotoxins target pathogenic cells, such as tumor cells, that carry a specific antigen recognized by an antibody (Olsnes, S., Immunol. Today, 10, pp. 291-295, 1989; Melby, EL, Cancer Res., 53(8), pp. 1755-1760, 1993; Better, MD, PCT Publication No. WO 91 / 07418, published May 30, 1991).

[0005] Another approach to target a group of pathogenic cells, such as cancer cells or foreign pathogens, in a host is to enhance the host immune response to pathogenic cells, thereby avoiding the need to administer compounds that may also exhibit independent host toxicity.One strategy reported for immunotherapy is to bind antibodies, such as genetically engineered multimeric antibodies, to the surface of tumor cells, and present the constant region of the antibody on the cell surface, thereby inducing tumor cell death through various immune system-mediated processes (De Vita, VT, Biologic Therapy of Cancer, 2nd ed. Philadelphia, Lippincott, 1995; Soulillou, JP, U.S. Patent No. 5,672,486).However, these approaches are complicated by the difficulty in defining tumor-specific antigens.

[0006] Another approach that has recently attracted interest is the delivery of radioisotopes of certain metals to patients. Such approaches have been applied to functional nanoparticles, antibodies, and small molecule conjugates (see, e.g., Teo MY, Morris MJ, “Prostate-Specific Membrane Antigen-Directed Therapy for Metastatic Castration-Resistant Prostate Cancer,” Cancer J. 2016;22(5):347-352; Jeon J., “Review of Therapeutic Applications of Radiolabeled Functional Nanomaterials,” Int J Mol Sci. 2019;20(9):2323; and Steiner, M, Neri, D., “Antibody-Radionuclide Conjugates for Cancer Therapy: Historical Considerations and New Trends,” Clin Cancer Res October 15, 2011 (17)(20) 6406-6416). These approaches have met with varying success within the wide variety of known cancers and known cancer drivers. Given the diversity of cancer types and cancer drivers, there is continued interest and a large unmet need for novel approaches to radiotherapeutics.

[0007] Folate plays an important role in nucleotide biosynthesis and cell division, intracellular activities occurring in both malignant and certain normal cells. Folate receptors have a high affinity for folate, which influences the cell cycle during cell division upon binding to the folate receptor. Folate receptors have been implicated in a variety of common tumor types, including ovarian, brain, lung, kidney, and colorectal cancers, which have been shown to exhibit high folate receptor expression. In contrast, folate receptor expression in normal tissues is limited, with the notable exception of the kidney. Folate receptor (FR) targeting is an attractive strategy for novel therapies, but FR-targeted radionuclide therapy has not yet become feasible. This is primarily due to the generally high accumulation of FR-targeted radioconjugates in the kidney and the associated potential for kidney tissue damage. There is a significant need for the development of FR-targeted radioconjugates, particularly those with reduced renal uptake, FR-targeted radionuclide therapy using these radioconjugates, and methods for diagnosing and imaging FR-positive cancers. Summary of the Invention

[0008] The present disclosure includes FR-targeted radioconjugates for FR-targeted radionuclide therapy, diagnosis and imaging of FR-positive cancer.The present disclosure also includes pharmaceutical compositions and combination medicines with these FR-targeted compounds.When used for treatment, FR-targeted compounds are usually complexed with radioactive elements, for example, chelating groups in the compound. 225 Ac or 177 When used for diagnostic or imaging purposes, FR targeting compounds typically contain a radioactive element, or a chelated Si- 18 F, B- 18 F or Al- 18 The compound may be a radioactive element suitable for diagnostic imaging, which may be F, or a radiolabeled prosthetic group.

[0009] Various embodiments of the present invention are described herein.

[0010] In certain embodiments, the compounds of formula (I) BL-(L x ) k -A(I), or a pharmaceutically acceptable salt thereof (In the formula, BL is a folate receptor binding ligand; A is a metal, radioactive element, Si- 18 F, B- 18 F or Al- 18 A is a chelating group Ch which may contain F, or A is a radiolabeled prosthetic group PG; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each L X are independently, AA, L 1 , L 2 or L 3 is selected from each AA is independently an amino acid residue; Each L 1 , L 2 and L 3 are independently as provided herein in embodiments of the present disclosure.

[0011] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present disclosure, eg, of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0012] In another aspect, the present invention provides combinations, particularly pharmaceutical combinations, comprising a compound of the present disclosure, for example of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically active agents.

[0013] In another aspect, the present invention provides a method for treating folate receptor (FR)-expressing tumors or cells, comprising contacting one or more FR-expressing tumors or cells with an effective amount of a compound of the present disclosure, e.g., of formula (I), or a pharmaceutically acceptable salt thereof, or with an effective amount of a pharmaceutical composition of the present disclosure, wherein the compound comprises a radiolabeled prosthetic group or a chelating group that chelates a radioactive element.

[0014] In another aspect, the present invention provides a method for treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of the present disclosure, wherein the compound comprises a radiolabeled prosthetic group or a chelating group that chelates a radioactive element.

[0015] In another aspect, the present invention provides a method for diagnostic imaging of FR-expressing cells (e.g., abnormal cell growth or tumors associated with FR-expressing cancer) in a subject, the method comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of the present disclosure, in an amount effective to diagnostically image the abnormal cell growth, wherein the compound comprises a metal, a radioactive element, or a radioactive halogen. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a chart showing the relative affinity of test compounds for folate receptor-positive KB cells at various concentrations after a 1-hour incubation period: (●) folic acid; (▲) compound 37; (■) compound 34. [Figure 2] A chart showing the binding affinity of Compound 37 and Compound 34 in folate receptor-positive KB cells at various concentrations: (◆) [177Lu]-Compound 37 (Kd=8.99 nM); (■) [177Lu]-Compound 34 (Kd=7.21 nM). [Figure 3] 1 is a chart showing the results of in vivo biodistribution analysis of 200 nmol / kg doses of [177Lu]-Compound 45, [177Lu]-Compound 17, and [177Lu]-Compound 68, and 300 nmol / kg doses of [177Lu]-Compound 37 and [177Lu]-Compound 34, 24 hours after injection in female nu / nu mice bearing folate receptor-positive M109 tumors. [Figure 4]4 is a chart providing tumor-to-kidney ratios corresponding to the results of the biodistribution analysis shown in FIG. 3 for compounds [177Lu]-Compound 45, [177Lu]-Compound 17, [177Lu]-Compound 68, [177Lu]-Compound 37, and [177Lu]-Compound 34. [Figure 5] 1 is a chart showing the antitumor activity of [177Lu]-Compound 37 and [177Lu]-Compound 34 at 300 nmol / 3.7 GBq / kg in female nu / nu mice bearing MDA-MB-231 tumors (n=5); four partial responses (PR) and one complete response (CR) were observed for [177Lu]-Compound 37, and five PRs were observed for [177Lu]-Compound 34; (■) control; (▲) [177Lu]-Compound 37; (●) [177Lu]-Compound 34. [Figure 6] 6 is a chart showing the average weights of mice from the study in Figure 5. Results indicate that the treatment was well tolerated; mice in both treatment groups did not experience significant weight loss immediately after or after administration; (■) control; (▲) [177Lu]-Compound 37; (●) [177Lu]-Compound 34. [Figure 7] 1 is a chart showing the antitumor activity of [225Ac]-Compound 5 at 100 nmol / 30 mCi / kg in mice bearing MDA-MB-231 tumors. The results show that treatment with [225Ac]-Compound 5 resulted in 50% complete responses and 50% partial responses. (■) Control; (●) [225Ac]-Compound 5. [Figure 8] 1 is a chart showing the antitumor activity of [225Ac]-Compound 5 at 100 nmol / 30 mCi / kg in mice bearing KB tumors. The results show that treatment with [225Ac]-Compound 5 resulted in 80% partial responses and 20% stable disease. (■) Control; (●) [225Ac]-Compound 5. [Figure 9]1 is a chart showing the results of in vivo biodistribution analysis of a 600 nmol / kg dose of [177Lu]-Compound 37 and [177Lu]-Compound 34 in female athymic nude-Foxn1nu mice bearing folate receptor-positive IGROV-1 tumors 4 and 24 hours after injection; specifically, the percentage of injected dose per gram of tissue (%ID / g tissue) 4 and 24 hours after injection for various samples (mean ± SD). [Figure 10] 1 is a chart showing the results of in vivo biodistribution analysis, specifically the percentage of injected dose per gram of tissue (%ID / g) at different time points (30 min, 1 h, 4 h, 24 h, 48 h, and 72 h) after injection of a mass dose of 100 nmol / kg BW of [177Lu]-Compound 34 in female athymic nude-Foxn1nu mice. [Figure 11] 1 is a chart showing the results of in vivo biodistribution analysis, specifically the percentage of injected dose per gram of tissue (%ID / g) at different time points (30 min, 1 h, 4 h, 24 h, 48 h, and 72 h) after injection of a mass dose of 200 nmol / kg BW of [177Lu]-Compound 34 in female athymic nude-Foxn1nu mice. [Figure 12] 1 is a chart showing the results of in vivo biodistribution analysis, specifically the percentage of injected dose per gram of tissue (%ID / g) at different time points (30 min, 1 h, 4 h, 24 h, 48 h, and 72 h) after injection of a mass dose of 200 nmol / kg BW of [177Lu]-Compound 34 in female athymic nude-Foxn1nu mice. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present disclosure includes FR-targeted radioconjugates (also referred to as "FR-targeted compounds" or "compounds"), compositions thereof, and combinations thereof for therapy, diagnosis, and imaging of proliferative diseases such as FR-expressing cancers.

[0018] In certain embodiments, the compounds of formula (I) BL-(L x ) k -A(I) (In the formula, BL is a folate receptor binding ligand; A is a metal, radioactive element, Si- 18 F, B- 18 F or Al- 18 A is a chelating group Ch which may contain F, or A is a radiolabeled prosthetic group PG; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each L X are independently, AA, L 1 , L 2 or L 3 and each AA is independently an amino acid residue; Each L 1 are independently expressed as [ka] (In the formula, R 16 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)R 19 , -C(O)OR 19 and -C(O)NR 19 R 19’ and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, -OR 20 , -OC(O)R 20 , -OC(O)NR 20 R 20’ , -OS(O)R 20 , -OS(O)2R 20 , -SR 20 , -S(O)R 20 , -S(O)2R 20 , -S(O)NR 20 R 20’ , -S(O)NR 20 R 20’ , -OS(O)NR 20 R20’ , -OS(O)2NR 20 R 20’ , -NR 20 R 20’ , -NR 20 C(O)R 21 , -NR 20 C(O)OR 21 , -NR 20 C(O)NR 21 R 21’ , -NR 20 S(O)R 21 , -NR 20 S(O)2R 21 , -NR 20 S(O)NR 21 R 21’ , -NR 20 S(O)NR 21 R 21’ , -C(O)R 20 , -C(O)OR 20 or -C(O)NR 20 R 20’ independently and optionally replaced by; Each R 17 and R 17’ are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 22 , -OC(O)R 22 , -OC(O)NR 22 R 22’ , -OS(O)R 22 , -OS(O)2R 22 , -SR 22 , -S(O)R 22 , -S(O)2R 22 , -S(O)NR 22 R 22’ , -S(O)NR 22 R 22’ , -OS(O)NR 22 R 22’ , -OS(O)2NR 22 R 22’ , -NR 22 R 22’ , -NR 22 C(O)R23 , -NR 22 C(O)OR 23 , -NR 22 C(O)NR 23 R 23’ , -NR 22 S(O)R 23 , -NR 22 S(O)2R 23 , -NR 22 S(O)NR 23 R 23’ , -NR 22 S(O)NR 23 R 23’ , -C(O)R 22 , -C(O)OR 22 , and -C(O)NR 22 R 22’ and selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 7-membered heteroaryl can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR 24 , -OC(O)R 24 , -OC(O)NR 24 R 24’ , -OS(O)R 24 , -OS(O)2R 24 , -SR 24 , -S(O)R 24 , -S(O)2R 24 , -S(O)NR 24 R 24’ , -S(O)NR 24 R 24’ , -OS(O)NR 24 R 24’ , -OS(O)2NR 24 R 24’ , -NR 24 R 24’ , -NR 24 C(O)R 25 , -NR 24 C(O)OR 25 , -NR 24 C(O)NR 25 R 25’ , -NR 24 S(O)R25 , -NR 24 S(O)2R 25 , -NR 24 S(O)NR 25 R 25’ , -NR 24 S(O)NR 25 R 25’ , -C(O)R 24 , -C(O)OR 24 or -C(O)NR 24 R 24’ or R 17 and R 17’ may be combined to form a C4-C6 cycloalkyl or a 4- to 6-membered heterocycle, and each hydrogen atom in the C4-C6 cycloalkyl or the 4- to 6-membered heterocycle may be replaced by a halogen, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C3-C6 cycloalkyl, a 3- to 7-membered heterocycloalkyl, a C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 24 , -OC(O)R 24 , -OC(O)NR 24 R 24’ , -OS(O)R 24 , -OS(O)2R 24 , -SR 24 , -S(O)R 24 , -S(O)2R 24 , -S(O)NR 24 R 24’ , -S(O)NR 24 R 24’ , -OS(O)NR 24 R 24’ , -OS(O)2NR 24 R 24’ , -NR 24 R 24’ , -NR 24 C(O)R 25 , -NR 24 C(O)OR 25 , -NR 24 C(O)NR 25 R 25’ , -NR 24 S(O)R 25 , -NR 24 S(O)2R 25 , -NR 24S(O)NR 25 R 25’ , -NR 24 S(O)NR 25 R 25’ , -C(O)R 24 , -C(O)OR 24 or -C(O)NR 24 R 24’ independently and optionally replaced by; R 18 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 26 , -OC(O)R 26 , -OC(O)NR 26 R 26’ , -OS(O)R 26 , -OS(O)2R 26 , -SR 26 , -S(O)R 26 , -S(O)2R 26 , -S(O)NR 26 R 26’ , -S(O)NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O)2NR 26 R 26’ , -NR 26 R 26’ , -NR 26 C(O)R 27 , -NR 26 C(O)OR 27 , -NR 26 C(O)NR 27 R 27’ , -NR 26 C(=NR 26’’ )NR 27 R 27’ , -NR 26 S(O)R 27 , -NR 26 S(O)2R 27 , -NR 26 S(O)NR 27 R 27’ , -NR 26 S(O)NR 27 R27’ , -C(O)R 26 , -C(O)OR 26 and -C(O)NR 26 R 26’ and selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 7-membered heteroaryl can be replaced by a halogen, a C1-C6 alkyl, a C2-C6 alkenyl, -(CH2) p OR 28 , -(CH2) p (OCH2) q OR 28 , -(CH2) p (OCH2CH2) q OR 28 , -OR 29 , -OC(O)R 29 , -OC(O)NR 29 R 29’ , -OS(O)R 29 , -OS(O)2R 29 , -(CH2) p OS(O)2OR 29 , -OS(O)2OR 29 , -SR 29 , -S(O)R 29 , -S(O)2R 29 , -S(O)NR 29 R 29’ , -S(O)NR 29 R 29’ , -OS(O)NR 29 R 29’ , -OS(O)2NR 29 R 29’ , -NR 29 R 29’ , -NR 29 C(O)R 30 , -NR 29 C(O)OR 30 , -NR 29 C(O)NR 30 R 30’ , -NR 29 S(O)R 30 , -NR 29 S(O)2R 30 , -NR 29S(O)NR 30 R 30’ , -NR 29 S(O)NR 30 R 30’ , -C(O)R 29 , -C(O)OR 29 or -C(O)NR 29 R 29’ independently and optionally replaced by; Each R 19 , R 19’ , R 20 , R 20’ , R 21 , R 21’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ are independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl and 5- to 7-membered heteroaryl, and is selected from the group consisting of C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 each hydrogen atom in the aryl or 5- to 7-membered heteroaryl is independently optionally replaced with halogen, —OH, —SH, —NH2, or —CO2H; R 27 and R 27’ are each independently H, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C3-C6 cycloalkyl, -(CH2) p (sugar), -(CH2) p (OCH2CH2) q -(sugar) and -(CH2) p (OCH2CH2CH2) q(sugars); R 28 is H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5-7 membered heteroaryl, or sugar; w is 1, 2, 3, 4 or 5; p is 1, 2, 3, 4 or 5; q is 1, 2, 3, 4 or 5; Each L 2 are independently expressed as [ka] (In the formula, Each R 31 and R 31’ are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 , -OS(O)2R 32 , -SR 32 , -S(O)R 32 , -S(O)2R 32 , -S(O)NR 32 R 32’ , -S(O)NR 32 R 32’ , -OS(O)NR 32 R 32’ , -OS(O)2NR 32 R 32’ , -NR 32 R 32’ , -NR 32 C(O)R33 , -NR 32 C(O)OR 33 , -NR 32 C(O)NR 33 R 33’ , -NR 32 S(O)R 33 , -NR 32 S(O)2R 33 , -NR 32 S(O)NR 33 R 33’ , -NR 32 S(O)NR 33 R 33’ , -C(O)R 32 , -C(O)OR 32 or -C(O)NR 32 R 32’ independently and optionally replaced by; X 6 is C1 to C6 alkyl or C6 to C 10 Aryl (C1-C6 alkyl), C1-C6 alkyl and C6-C 10 Each hydrogen atom in aryl(C1-C6 alkyl) can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 34 , -OC(O)R 34 , -OC(O)NR 34 R 34’ , -OS(O)R 34 , -OS(O)2R 34 , -SR 34 , -S(O)R 34 , -S(O)2R 34 , -S(O)NR 34 R 34’ , -S(O)NR 34 R 34’ , -OS(O)NR 34 R 34’ , -OS(O)2NR 34 R 34’ , -NR 34 R 34’ , -NR 34 C(O)R 35 , -NR 34 C(O)OR35 , -NR 34 C(O)NR 35 R 35’ , -NR 34 S(O)R 35 , -NR 34 S(O)2R 35 , -NR 34 S(O)NR 35 R 35’ , -NR 34 S(O)NR 35 R 35’ , -C(O)R 34 , -C(O)OR 34 or -C(O)NR 34 R 34’ independently and optionally replaced by; Each R 32 , R 32’ , R 33 , R 33’ , R 34 , R 34’ , R 35 and R 35’ are independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl, and 5- to 7-membered heteroaryl; R 36 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 , -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR 37 , -S(O)R 37 , -S(O)2R 37, -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; R 37 , R 37’ , R 38 and R 38’ are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl and 5- to 7-membered heteroaryl); Each L 3 are independently C1-C6 alkylene, -OC1-C6 alkylene, -SC1-C6 alkylene, C3-C6 cycloalkylene, -C(O)C3-C6 cycloalkylene-, -C(O)C3-C6 cycloalkylene-(CR 39 R 39’ ) r -, -C(O)C3-C6 cycloalkylene-(CR 39 R 39’ ) r NR37 -, 3-7 membered heterocycloalkylene, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -NR 36 (CR 36’ R 36’’ ) r -S-(succinimidyl)-, -(CR 36’ R 36’’ ) r C(O)NR 37 -, -(CR 39 R 39’ ) r C(O)-, -(CR 39 R 39’ ) r OC(O)-, -S(CR 39 R 39’ ) r OC(O)-, -C(O)(CR 39 R 39’ ) r -, -C(O)O(CR 39 R 39’ ) r -, -NR 37 C(O)(CR 39 R 39’ ) r -,-(CR 39 R 39’ ) r C(O)NR 37 -, -NR 37 C(O)(CR 39’ R 39’’ ) r S-, -NR 37 (CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r NR 38 -, -NR 37 (CR 39 R 39’ ) r NR 38 -, -NR 37 (CR 39 R 39’ ) r S-, -NR 37 (CR 39 R 39’ CR 39 R39’ O) r -、-NR 37 (CR 39 R 39’ CR 39 R 39’ O) rp -(CR 36 R 36’ ) t C(O)-、-C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NR 37 -、-(CR 39 R 39’ CR 39 R 39’ O) r -(CR 36 R 36’ ) t C(O)-、-C(O)(CR 36 R 36’ ) t (OCR 39 R 39’ CR 39 R 39’ CR 39 R 39’ ) r -、-C(O)(CR 36 R 36’ ) t (OCR 39 R 39’ CR 39 R 39’ CR 39 R 39’ ) r NR 37 -、-C(O)(CR 36 R 36’ ) r -O-(C6~C 10 アリール)-(CR 36’’ R 36’’’ ) t NR 37 -、-NR 37 (CR 36 R 36’ ) r -(C6~C 10 アリール)-O-(CR 36’’ R36’’’ ) t C(O)-, -C(O)-(CR 36 R 36’ ) r -NR 37 -C(O)-(C6~C 10 (aryl)-NR 37’ -, -NR 37 -(C6~C 10 Aryl)-C(O)-NR 37’ -(CR 36 R 36’ ) r -C(O)-, -NR 37 (CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NR 37 -, -NR 37 (CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NR 37’ - or -NR 37’ -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NR 37 - and C6~C 10 Each hydrogen atom in the aryl can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37, -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR 37 , -S(O)R 37 , -S(O)2R 37 , -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; During the ceremony, Each R 36 , R 36’ , R 36’’ and R 36’’’ are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C(O)R 37 , -C(O)OR 37 and -C(O)NR 37 R 37’and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 , -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR 37 , -S(O)R 37 , -S(O)2R 37 , -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; R 37 , R 37’ , R 38 and R 38’are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl and 5- to 7-membered heteroaryl; Each R 39 and R 39’ are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 40 , -OC(O)R 40 , -OC(O)NR 40 R 40’ , -OS(O)R 40 , -OS(O)2R 40 , -SR 40 , -S(O)R 40 , -S(O)2R 40 , -S(O)NR 40 R 40’ , -S(O)NR 40 R 40’ , -OS(O)NR 40 R 40’ , -OS(O)2NR 40 R 40’ , -NR 40 R 40’ , -NR 40 C(O)R 41 , -NR 40 C(O)OR 41 , -NR 40 C(O)NR 41 R 41’ , -NR 40 S(O)R 41 , -NR 40 S(O)2R 41 , -NR 40 S(O)NR 41 R 41’ , -NR 40 S(O)NR 41 R 41’ , -C(O)R 40 , -C(O)OR 40 and -C(O)NR 40 R 40’selected from the group consisting of: R 40 , R 40’ , R 41 and R 41’ are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl and 5- to 7-membered heteroaryl; each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each rp is independently an integer from 1 to 80; and each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each * represents a covalent bond; For k greater than 3, L in formula (I) x At least two of the following are independent: [ka] selected from; and The compound is [ka] , tautomers of (E1) to (E5), compounds of (E1) to (E5) to which a metal or radioactive element is chelated, or pharmaceutical salts of (E1) to (E5)) or a pharmaceutically acceptable salt thereof.

[0019] Unless otherwise specified, the term "compounds of the disclosure" or "compound of the disclosure" refers to compounds of Formula (I), subformulas thereof, and exemplified compounds, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution), and inherently formed moieties.

[0020] The present disclosure provides the following exemplary embodiments: Embodiment 1: Compound of Formula (I) BL-(L x ) k -A(I), or a pharmaceutically acceptable salt thereof (In the formula, BL is a folate receptor binding ligand; A is a metal, radioactive element, Si- 18 F, B- 18 F or Al- 18 A is a chelating group Ch which may contain F, or A is a radiolabeled prosthetic group PG; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each L X are independently, AA, L 1 , L 2 or L 3 and each AA is independently an amino acid residue; Each L 1 are independently expressed as [ka] (In the formula, R 16 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)R 19 , -C(O)OR 19 and -C(O)NR 19 R 19’ and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, -OR 20 , -OC(O)R 20 , -OC(O)NR 20 R 20’ , -OS(O)R 20 , -OS(O)2R 20 , -SR 20 , -S(O)R 20 , -S(O)2R 20 , -S(O)NR 20 R 20’ , -S(O)NR20 R 20’ , -OS(O)NR 20 R 20’ , -OS(O)2NR 20 R 20’ , -NR 20 R 20’ , -NR 20 C(O)R 21 , -NR 20 C(O)OR 21 , -NR 20 C(O)NR 21 R 21’ , -NR 20 S(O)R 21 , -NR 20 S(O)2R 21 , -NR 20 S(O)NR 21 R 21’ , -NR 20 S(O)NR 21 R 21’ , -C(O)R 20 , -C(O)OR 20 or -C(O)NR 20 R 20’ independently and optionally replaced by; Each R 17 and R 17’ are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 22 , -OC(O)R 22 , -OC(O)NR 22 R 22’ , -OS(O)R 22 , -OS(O)2R 22 , -SR 22 , -S(O)R 22 , -S(O)2R 22 , -S(O)NR 22 R 22’ , -S(O)NR 22 R 22’ , -OS(O)NR 22 R 22’ , -OS(O)2NR 22 R 22’ , -NR22 R 22’ , -NR 22 C(O)R 23 , -NR 22 C(O)OR 23 , -NR 22 C(O)NR 23 R 23’ , -NR 22 S(O)R 23 , -NR 22 S(O)2R 23 , -NR 22 S(O)NR 23 R 23’ , -NR 22 S(O)NR 23 R 23’ , -C(O)R 22 , -C(O)OR 22 , and -C(O)NR 22 R 22’ and selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 7-membered heteroaryl can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR 24 , -OC(O)R 24 , -OC(O)NR 24 R 24’ , -OS(O)R 24 , -OS(O)2R 24 , -SR 24 , -S(O)R 24 , -S(O)2R 24 , -S(O)NR 24 R 24’ , -S(O)NR 24 R 24’ , -OS(O)NR 24 R 24’ , -OS(O)2NR 24 R 24’ , -NR 24 R 24’ , -NR 24 C(O)R 25 , -NR 24 C(O)OR 25 , -NR 24 C(O)NR25 R 25’ , -NR 24 S(O)R 25 , -NR 24 S(O)2R 25 , -NR 24 S(O)NR 25 R 25’ , -NR 24 S(O)NR 25 R 25’ , -C(O)R 24 , -C(O)OR 24 or -C(O)NR 24 R 24’ or R 17 and R 17’ may be combined to form a C4-C6 cycloalkyl or a 4- to 6-membered heterocycle, and each hydrogen atom in the C4-C6 cycloalkyl or the 4- to 6-membered heterocycle may be replaced by a halogen, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C3-C6 cycloalkyl, a 3- to 7-membered heterocycloalkyl, a C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 24 , -OC(O)R 24 , -OC(O)NR 24 R 24’ , -OS(O)R 24 , -OS(O)2R 24 , -SR 24 , -S(O)R 24 , -S(O)2R 24 , -S(O)NR 24 R 24’ , -S(O)NR 24 R 24’ , -OS(O)NR 24 R 24’ , -OS(O)2NR 24 R 24’ , -NR 24 R 24’ , -NR 24 C(O)R 25 , -NR 24 C(O)OR 25 , -NR 24 C(O)NR 25 R 25’ , -NR 24 S(O)R 25, -NR 24 S(O)2R 25 , -NR 24 S(O)NR 25 R 25’ , -NR 24 S(O)NR 25 R 25’ , -C(O)R 24 , -C(O)OR 24 or -C(O)NR 24 R 24’ independently and optionally replaced by; R 18 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 26 , -OC(O)R 26 , -OC(O)NR 26 R 26’ , -OS(O)R 26 , -OS(O)2R 26 , -SR 26 , -S(O)R 26 , -S(O)2R 26 , -S(O)NR 26 R 26’ , -S(O)NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O)2NR 26 R 26’ , -NR 26 R 26’ , -NR 26 C(O)R 27 , -NR 26 C(O)OR 27 , -NR 26 C(O)NR 27 R 27’ , -NR 26 C(=NR 26’’ )NR 27 R 27’ , -NR 26 S(O)R 27 , -NR 26 S(O)2R 27 , -NR 26 S(O)NR 27R 27’ , -NR 26 S(O)NR 27 R 27’ , -C(O)R 26 , -C(O)OR 26 and -C(O)NR 26 R 26’ and selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 7-membered heteroaryl can be replaced by a halogen, a C1-C6 alkyl, a C2-C6 alkenyl, -(CH2) p OR 28 , -(CH2) p (OCH2) q OR 28 , -(CH2) p (OCH2CH2) q OR 28 , -OR 29 , -OC(O)R 29 , -OC(O)NR 29 R 29’ , -OS(O)R 29 , -OS(O)2R 29 , -(CH2) p OS(O)2OR 29 , -OS(O)2OR 29 , -SR 29 , -S(O)R 29 , -S(O)2R 29 , -S(O)NR 29 R 29’ , -S(O)NR 29 R 29’ , -OS(O)NR 29 R 29’ , -OS(O)2NR 29 R 29’ , -NR 29 R 29’ , -NR 29 C(O)R 30 , -NR 29 C(O)OR 30 , -NR 29 C(O)NR 30 R 30’ , -NR 29 S(O)R 30, -NR 29 S(O)2R 30 , -NR 29 S(O)NR 30 R 30’ , -NR 29 S(O)NR 30 R 30’ , -C(O)R 29 , -C(O)OR 29 or -C(O)NR 29 R 29’ independently and optionally replaced by; Each R 19 , R 19’ , R 20 , R 20’ , R 21 , R 21’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ are independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl and 5- to 7-membered heteroaryl, and is selected from the group consisting of C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 each hydrogen atom in the aryl or 5- to 7-membered heteroaryl is independently optionally replaced with halogen, —OH, —SH, —NH2, or —CO2H; R 27 and R 27’ are each independently H, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C3-C6 cycloalkyl, -(CH2) p (sugar), -(CH2) p (OCH2CH2) q-(sugar) and -(CH2) p (OCH2CH2CH2) q (sugars); R 28 is H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5-7 membered heteroaryl, or sugar; w is 1, 2, 3, 4 or 5; p is 1, 2, 3, 4 or 5; q is 1, 2, 3, 4 or 5; Each L 2 are independently expressed as [ka] (In the formula, Each R 31 and R 31’ are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 , -OS(O)2R 32 , -SR 32 , -S(O)R 32 , -S(O)2R 32 , -S(O)NR 32 R 32’ , -S(O)NR 32 R 32’ , -OS(O)NR 32 R 32’ , -OS(O)2NR 32 R 32’ , -NR32 R 32’ , -NR 32 C(O)R 33 , -NR 32 C(O)OR 33 , -NR 32 C(O)NR 33 R 33’ , -NR 32 S(O)R 33 , -NR 32 S(O)2R 33 , -NR 32 S(O)NR 33 R 33’ , -NR 32 S(O)NR 33 R 33’ , -C(O)R 32 , -C(O)OR 32 or -C(O)NR 32 R 32’ independently and optionally replaced by; X 6 is C1 to C6 alkyl or C6 to C 10 Aryl (C1-C6 alkyl), C1-C6 alkyl and C6-C 10 Each hydrogen atom in aryl(C1-C6 alkyl) can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 34 , -OC(O)R 34 , -OC(O)NR 34 R 34’ , -OS(O)R 34 , -OS(O)2R 34 , -SR 34 , -S(O)R 34 , -S(O)2R 34 , -S(O)NR 34 R 34’ , -S(O)NR 34 R 34’ , -OS(O)NR 34 R 34’ , -OS(O)2NR 34 R 34’ , -NR 34 R 34’ , -NR34 C(O)R 35 , -NR 34 C(O)OR 35 , -NR 34 C(O)NR 35 R 35’ , -NR 34 S(O)R 35 , -NR 34 S(O)2R 35 , -NR 34 S(O)NR 35 R 35’ , -NR 34 S(O)NR 35 R 35’ , -C(O)R 34 , -C(O)OR 34 or -C(O)NR 34 R 34’ independently and optionally replaced by; Each R 32 , R 32’ , R 33 , R 33’ , R 34 , R 34’ , R 35 and R 35’ are independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl, and 5- to 7-membered heteroaryl; R 36 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 , -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR37 , -S(O)R 37 , -S(O)2R 37 , -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; R 37 , R 37’ , R 38 and R 38’ are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl and 5- to 7-membered heteroaryl); Each L 3 are independently C1-C6 alkylene, -OC1-C6 alkylene, -SC1-C6 alkylene, C3-C6 cycloalkylene, -C(O)C3-C6 cycloalkylene-, -C(O)C3-C6 cycloalkylene-(CR 39 R 39’ ) r-, -C(O)C3-C6 cycloalkylene-(CR 39 R 39’ ) r NR 37 -, 3-7 membered heterocycloalkylene, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -NR 36 (CR 36’ R 36’’ ) r -S-(succinimidyl)-, -(CR 36’ R 36’’ ) r C(O)NR 37 -, -(CR 39 R 39’ ) r C(O)-, -(CR 39 R 39’ ) r OC(O)-, -S(CR 39 R 39’ ) r OC(O)-, -C(O)(CR 39 R 39’ ) r -, -C(O)O(CR 39 R 39’ ) r -, -NR 37 C(O)(CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r C(O)NR 37 -, -NR 37 C(O)(CR 39’ R 39’’ ) r S-, -NR 37 (CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r NR 38 -, -NR 37 (CR 39 R 39’ ) r NR 38 -, -NR 37 (CR 39 R 39’ ) r S-, -NR37 (CR 39 R 39’ CR 39 R 39’ O) r -、-NR 37 (CR 39 R 39’ CR 39 R 39’ O) rp -(CR 36 R 36’ ) t C(O)-、-C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NR 37 -、-(CR 39 R 39’ CR 39 R 39’ O) r -(CR 36 R 36’ ) t C(O)-、-C(O)(CR 36 R 36’ ) t (OCR 39 R 39’ CR 39 R 39’ CR 39 R 39’ ) r -、-C(O)(CR 36 R 36’ ) t (OCR 39 R 39’ CR 39 R 39’ CR 39 R 39’ ) r NR 37 -、-C(O)(CR 36 R 36’ ) r -O-(C6~C 10 アリール)-(CR 36’’ R 36’’’ ) t NR 37 -、-NR 37 (CR 36 R 36’) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t C(O)-, -C(O)-(CR 36 R 36’ ) r -NR 37 -C(O)-(C6~C 10 (aryl)-NR 37’ -, -NR 37 -(C6~C 10 Aryl)-C(O)-NR 37’ -(CR 36 R 36’ ) r -C(O)-, -NR 37 (CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NR 37 -, -NR 37 (CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NR 37’ - or -NR 37’ -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NR 37 - and C6~C 10 Each hydrogen atom in the aryl can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10Aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 , -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR 37 , -S(O)R 37 , -S(O)2R 37 , -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; During the ceremony, Each R 36 , R 36’ , R 36’’ and R 36’’’ are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C(O)R 37 , -C(O)OR 37 and -C(O)NR 37 R 37’and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 , -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR 37 , -S(O)R 37 , -S(O)2R 37 , -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; R 37 , R 37’ , R 38 and R 38’are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl and 5- to 7-membered heteroaryl; Each R 39 and R 39’ are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 40 , -OC(O)R 40 , -OC(O)NR 40 R 40’ , -OS(O)R 40 , -OS(O)2R 40 , -SR 40 , -S(O)R 40 , -S(O)2R 40 , -S(O)NR 40 R 40’ , -S(O)NR 40 R 40’ , -OS(O)NR 40 R 40’ , -OS(O)2NR 40 R 40’ , -NR 40 R 40’ , -NR 40 C(O)R 41 , -NR 40 C(O)OR 41 , -NR 40 C(O)NR 41 R 41’ , -NR 40 S(O)R 41 , -NR 40 S(O)2R 41 , -NR 40 S(O)NR 41 R 41’ , -NR 40 S(O)NR 41 R 41’ , -C(O)R 40 , -C(O)OR 40 and -C(O)NR 40 R 40’selected from the group consisting of: R 40 , R 40’ , R 41 and R 41’ are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl and 5- to 7-membered heteroaryl; each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each rp is independently an integer from 1 to 80; and each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each * represents a covalent bond; For k greater than 3, L in formula (I) x At least two of the following are independent: [ka] selected from; and The compound is [ka] , tautomers of (E1) to (E5), compounds of (E1) to (E5) to which a metal or radioactive element is chelated, or pharmaceutical salts thereof).

[0021] Embodiment 2: A compound of embodiment 1, or a pharmaceutically acceptable salt thereof. (In the formula, Each L 1 are independently expressed as [ka] (In the formula, R 16 is H, Each R 17 and R 17’are independently H, C1-C6 alkyl, or —C(O)OH; Each R 18 are independently H, C6 to C 10 Aryl, -OH-SH, -NHC(=NH ’ )NH2 or -C(O)OH, C6 to C 10 each hydrogen atom in the aryl is independently optionally replaced by a halogen; Each L 2 are independently expressed as [ka] (In the formula, R 31 and R 31’ is H, R 36 is H; and Each L 3 are independently -C(O)C3-C6 cycloalkylene-(CH2) r NH-, -(CR 39 R 39’ ) r C(O)-, -C(O)(CR 39 R 39’ ) r -, -NH(CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r NH-, -NH(CR 39 R 39’ ) r NH-, -NH(CH2CH2O) rp -(CR 36 R 36’ ) t C(O)-, -C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NH-, -C(O)(CR 36 R 36’ ) r-O-(C6~C 10 Aryl)-(CR 36’’ R 36’’’ ) t NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t C(O)-, -C(O)-(CR 36 R 36’ ) r -NH-C(O)-(C6~C 10 Aryl)-NH-, -NR 37 -(C6~C 10 aryl)-C(O)-NH-(CR 36 R 36’ ) r -C(O)-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NH- or -NH-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-; During the ceremony, Each R 36 , R 36’ , R 36’’ , R 36’’’ , R 39 and R 39’are independently H or —COOH; each r is independently 1, 2, 3, 4, or 5; and Each t is independently 1, 2, 3, 4, or 5).

[0022] Embodiment 3: BL-(L x ) k -Ch, BL-L 3 -Ch, BL-L 1 -L 3 -Ch, BL-L 3 -L 3 -L 1 -L 1 -L 1 -L 3 -Ch, BL-L 3 -L 1 -Ch, BL-L 3 -L 3 -L 3 -Ch, BL-L 3 -L 3 -L 1 -L 3 -L 3 -Ch, BL-L 3 -L 1 -L 3 -Ch, BL-L 3 -L 3 -AA-L 1 -L 2 -L 3 -Ch, BL-L 3 -L 3 -L 1 -L 1 -L 1 -L 2 -Ch, BL-L 3 -L 3 -L 3 -L 1 -AA-Ch, BL-L 3 -L 3 -AA-Ch, BL-L 3 -L 3 -Ch, BL-L 3 -L 1 -AA-Ch, BL-L 3 -L 3 -L 3 -L 1 -Ch, BL-L 3 -L3 -L 3 -L 1 -L 1 -Ch, BL-L 3 -L 1 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch, BL-L 3 -AA-Ch, BL-L 3 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch, BL-L 3 -L 3 -L 3 -AA-Ch or BL-L 3 -L 3 -L 3 -L 3 -Ch and each AA is independently an amino acid residue; or a pharmaceutically acceptable salt thereof.

[0023] Embodiment 4: BL comprises one amino acid residue covalently linked to a pteryl group or derivative thereof, and BL-(L x ) k -Ch, BL-L 3 -Ch, BL-L 1 -L 1 -L 1 -L 3 -Ch, BL-L 1 -Ch, BL-L 3 -L 3 -Ch, BL-L 1 -L 3 -L 3 -Ch, BL-L 1 -L 3 -Ch, BL-L 3 -L 3 -AA-L 1 -L 2 -L 3 -Ch, BL-L 1 -L 1 -L 1 -L 2 -Ch, BL-L 3 -L 3 -L 1 -AA-Ch, BL-L 3-AA-Ch, BL-L 1 -AA-Ch, BL-L 3 -L 3 -L 1 -Ch, BL-L 3 -L 1 -Ch, BL-L 3 -L 3 -L 1 -L 1 -Ch, BL-L 3 -L 1 -L 1 -Ch, BL-L 1 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch, BL-AA-Ch, BL-L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch, or BL-L 1 -L 1 -L 1 -L 1 -L 2 -L 3 -L 1 -L 1 The compound of any one of embodiments 1-3, wherein -Ch and each AA is independently an amino acid residue, or a pharmaceutically acceptable salt thereof.

[0024] Embodiment 5: When k is greater than 4, L in formula (I) x At least three of the following are independent: [ka] 5. The compound of any one of embodiments 1-4, selected from:

[0025] Embodiment 6: When k is greater than 4, L in formula (I) x At least three of the following are independent: [ka] 5. The compound of any one of embodiments 1-4, selected from:

[0026] Embodiment 7: At least one L x but, [ka] 7. The compound of any one of embodiments 1-6, wherein:

[0027] Embodiment 8: BL-(L x ) k -Ch is a compound of the formula BL-L x -L a -L x -Ch, BL-L x -L x -L a -L x -Ch, BL-L x -L x -L a -Ch or BL-L x -L x -L a -L a -Ch and L a but, [ka] and each L x However, independently, AA, L 1 , or L 3 7. The compound of any one of embodiments 1-6, wherein:

[0028] Embodiment 9: BL-(L x ) k -Ch is a compound of the formula BL-L a -L x -Ch, BL-L x -L a -L x -Ch, BL-L x -L a -Ch or BL-L x -L a -La -Ch and L a but, [ka] and each L x However, independently, AA, L 1 , or L 3 7. The compound of any one of embodiments 1-6, wherein:

[0029] Embodiment 10: L a but, [ka] 10. The compound of embodiment 8 or 9, wherein:

[0030] Embodiment 11: At least one L x but, [ka] 7. The compound of any one of embodiments 1-6, wherein:

[0031] Embodiment 12: At least one L x but, [ka] 7. The compound of any one of embodiments 1-6, wherein:

[0032] Embodiment 13: BL-(L x ) k -Ch is a compound of the formula BL-L x -L b -L x -Ch, BL-L x -L b -Ch or BL-L x -L b -L b-Ch and L b but, [ka] and each L x However, independently, AA, L 1 , or L 3 7. The compound of any one of embodiments 1-6, wherein:

[0033] Embodiment 14: BL-(L x ) k -Ch is a compound of the formula BL-L b -L x -Ch, BL-L b -Ch or BL-L b -L b -Ch and L b but, [ka] and each L x However, independently, AA, L 1 , or L 3 7. The compound of any one of embodiments 1-6, wherein:

[0034] Embodiment 15: L b but, [ka] 15. The compound of embodiment 13 or 14, wherein:

[0035] Embodiment 16: The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein BL comprises a pteryl group or a derivative thereof.

[0036] Embodiment 17: BL is of the formula [ka] (In the formula, R 1 and R 2 is, in each instance, independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR 7 , -SR 7 and -NR 7 R 7’ and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is selected from the group consisting of halogen, -OR 8 , -SR 8 , -NR 8 R 8’ , -C(O)R 8 , -C(O)OR 8 or -C(O)NR 8 R 8’ independently and optionally replaced by; R 3 , R 4 , R 5 and R 6 are each independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CN, -NO2, -NCO, -OR 9 , -SR 9 , -NR 9 R 9’ , -C(O)R 9 , -C(O)OR 9 and -C(O)NR 9 R 9’ and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is selected from the group consisting of halogen, -OR 10 , -SR 10 , -NR 10 R 10’ , -C(O)R 10 , -C(O)OR 10 or -C(O)NR 10 R 10’ independently and optionally replaced by; Each R 7 , R 7’ , R 8 , R 8’ , R 9 , R 9’ , R 10and R 10’ are independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; X 1 is -N(R 11 )-, =N-, -N=, -C(R 11 )= or = C(R 11 )-and; X 2 is -N(R 11’ )- or =N-; X 3 is -N(R 11’’ )-, -N= or -C(R 11’ )=and; X 4 is -N= or -C=; X 5 is -N(R 12 )- or -C(R 12 )(R 12’ )-and; X 1 However, -N= or -C(R 11 )=, then Y 1 H, -OR 13 or -SR 13 or X 1 But, -NR 11 -, =N- or =C(R 11 )-, then Y 1 is =O; X 4 When -C=, Y 2 is H, C1-C6 alkyl, C2-C6 alkenyl, -C(O)R 14 , -C(O)OR 14 or -C(O)NR 14 R 14’ or X 4 When -N=, Y 2 does not exist; R 1’ , R 2’ , R 11 , R 11’ , R 11’’ , R 12 , R 12’ , R 13 , R 14 and R 14’are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)R 15 , -C(O)OR 15 and -C(O)NR 15 R 15’ selected from the group consisting of: R 15 and R 15’ are each independently H or C1-C6 alkyl; m is 1, 2, 3, or 4; and n is 0 or 1; The compound of any one of the preceding embodiments, wherein * represents a covalent bond to the remainder of the compound, or a pharmaceutically acceptable salt thereof.

[0037] Embodiment 18: The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0038] Embodiment 19:X 1 But, -NR 11 19. The compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein:

[0039] Embodiment 20:X 2 20. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein: is =N-.

[0040] Embodiment 21: Y 1 The compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein is =O.

[0041] Embodiment 22:X 1 But, -NR 11 - and R 11 22. The compound of any one of embodiments 1-21, wherein is H, or a pharmaceutically acceptable salt thereof.

[0042] Embodiment 23:X 3 But -C(R 11’23. The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein:

[0043] Embodiment 24:R 11’ is H, or a pharmaceutically acceptable salt thereof.

[0044] Embodiment 25:X 4 23. The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein is -C=.

[0045] Embodiment 26: Y 2 The compound of any one of embodiments 1-23, wherein is H, or a pharmaceutically acceptable salt thereof.

[0046] Embodiment 27:X 3 21. The compound of any one of embodiments 1-20, wherein is -N=, or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 28:X 4 28. The compound of any one of embodiments 1-22 or 27, wherein is -N=; or a pharmaceutically acceptable salt thereof.

[0048] Embodiment 29:X 5 But, -NR 12 29. The compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein:

[0049] Embodiment 30:R 12 The compound of any one of embodiments 1-29, wherein is H, or a pharmaceutically acceptable salt thereof.

[0050] Embodiment 31:R 1’ and R 2’ The compound of any one of embodiments 1-30, wherein is H, or a pharmaceutically acceptable salt thereof.

[0051] Embodiment 32: Each R 1 and R 2The compound of any one of embodiments 1-31, wherein is H, or a pharmaceutically acceptable salt thereof.

[0052] Embodiment 33:R 3 , R 4 , R 5 and R 6 The compound of any one of embodiments 1-32, wherein is H, or a pharmaceutically acceptable salt thereof.

[0053] Embodiment 34: The compound of any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0054] Embodiment 35: BL is of the formula [ka] 17. The compound of any one of embodiments 1-16, wherein n is 0 or 1 and AA is an amino acid residue, or a pharmaceutically acceptable salt thereof.

[0055] Embodiment 36: BL is of the formula [ka] 18. The compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein:

[0056] Embodiment 37: Ch is 111 In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 169 Er, 72 As, 97 Ru, 203 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y,51 Cr, 52m Mn, 177 Lu, 161 Tb, 169 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117m Sn, 213 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 123 I, 124 I, 125 I, 18 F, 149 Tb, 152 Tb, 155 Tb, 47 Sc, 44 Sc, 43 Sc, 225 Ac, 212 Pb, 211 At, 223 Ra, 227 Th, 131 I, 82 Rb, 76 As, 89 Zr, 111 Ag, 165 Er, 227 Ac, and 61 37. The compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, comprising a radioactive element selected from the group consisting of Cu.

[0057] Embodiment 38: Ch is 66 Ga, 67 Ga, 68 Ga, 177 Lu, and 225 The compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt thereof, comprising a radioactive element selected from the group consisting of Ac.

[0058] Embodiment 39: Ch is [ka] [ka] and Ch is selected from the group consisting of a radioactive element, Si- 18 F, B- 18 F or Al- 18 The compound of any one of the preceding embodiments, which may include F, or a salt thereof.

[0059] Embodiment 40: Ch [ka] and Ch is a radioactive element, Si- 18 F, B- 18 F or Al- 18 The compound of any one of the preceding embodiments, which may include F, or a pharmaceutically acceptable salt thereof.

[0060] Embodiment 41: BL comprises a pteryl group or a derivative thereof, and the pteryl group or derivative thereof is [ka] The compound of any one of embodiments 1-40, wherein the compound is covalently attached to a group selected from:

[0061] Embodiment 42: 1, 2 or 3 L x independently, w is 1 or 2, and R 18 C6~C 10 L is aryl 1 The compound of any one of embodiments 1-41, wherein each hydrogen is optionally substituted with halogen or C1-C6 alkyl.

[0062] Embodiment 43: 1, 2 or 3 L x But independently, the formula [ka] 43. The compound of embodiment 42, wherein

[0063] Embodiment 44: The compound has the formula (C1)-(C32): [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0064] Embodiment 45: The compound is represented by the formula (C1) to (C32) [ka] [ka] [ka] [ka] [ka] and L in any one of the formulae (C1) to (C32) is x One group corresponding to L is different xThe compound of embodiment 1, except replaced by:

[0065] Embodiment 46: Different L x One group replaced by a different L x are different AA groups, and the different AA groups are conservative amino acid substitutions for the AA groups; or a pharmaceutically acceptable salt thereof.

[0066] Embodiment 47:-(L x ) k - is a group of formula (III) [ka] 44. The compound of any one of embodiments 1-43, comprising:

[0067] Embodiment 48:R 16 , R 37 and R 38 The compound of embodiment 47, wherein is H.

[0068] Embodiment 49:R 39 The compound of embodiment 47 or 48, wherein is —COOH.

[0069] Embodiment 50: The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof; wherein the chelating group represented by the above structural formula is selected from the group consisting of a radioactive element, Si- 18 F, B- 18 F or Al- 18 The compound of embodiment 1, which may include F.

[0070] Embodiment 51: The compound has the formula [ka] or a pharmaceutically acceptable salt thereof.

[0071] Embodiment 52: The compound has the formula [ka] (Wherein M is 177 Lu or 225 Ac); or a pharmaceutically acceptable salt thereof.

[0072] Embodiment 53: The compound has the formula [ka] or a pharmaceutically acceptable salt thereof.

[0073] Embodiment 54: The compound has the formula [ka] (Wherein M is 177 Lu or 225 Ac); or a pharmaceutically acceptable salt thereof.

[0074] Embodiment 55: The compound has the formula [ka] and a carboxyl group at the β, γ, δ, ε, or ζ position relative to the carbonyl designated by "**" in the above formula; or a pharmaceutically acceptable salt thereof.

[0075] Embodiment 56: PG is 18 F, 75 Br, 76 Br, 77 Br, 80 Br, 80m Br, 82 Br, 123 I, 124 I, 125 I, 131 I and 211 51. The compound of any one of embodiments 1, 2, 5, 6, 7, 11, 12, 16-36, 41-43, 47-49, and 50, or a pharmaceutically acceptable salt thereof, labeled with a radioactive halogen selected from the group consisting of At.

[0076] Embodiment 57: A pharmaceutical composition comprising a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0077] Embodiment 58: A method for treating FR-expressing tumors or cells, comprising contacting one or more FR-expressing tumors or cells with an effective amount of a compound according to any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition of embodiment 57, wherein the compound comprises a chelating group that chelates a radioactive element.

[0078] Embodiment 59: The method of embodiment 58, wherein the FR-expressing tumor or cell is in vitro, in vivo, or ex vivo.

[0079] Embodiment 60: A method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 57, wherein the compound comprises a chelating group that chelates a radioactive element.

[0080] Embodiment 61: The method of embodiment 60, wherein the proliferative disease is cancer.

[0081] Embodiment 62: The method of embodiment 61, wherein the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphatic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, and pituitary adenoma.

[0082] Embodiment 63: The method of any one of embodiments 60-62, further comprising administering to the subject an effective amount of folic acid.

[0083] Embodiment 64: The method of any one of embodiments 60-63, further comprising administering to the subject an effective amount of an antifolate.

[0084] Embodiment 65: The method of any one of embodiments 60 to 64, further comprising administering to the subject an effective amount of a radiosensitizer.

[0085] Embodiment 66: The method of any one of embodiments 60 to 65, wherein the subject is a human.

[0086] Embodiment 67: Use of a compound according to any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.

[0087] Embodiment 68: A compound according to any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.

[0088] Embodiment 69: A method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 56, or a pharmaceutically acceptable salt thereof, or an effective amount of the pharmaceutical composition of embodiment 57 (wherein the compound comprises a metal, a radioactive element, or a radioactive halogen).

[0089] Embodiment 70: BL is of the formula [ka] and (AA) n or n is 0, then (L x ) k and (AA) in formula (II) n The compound according to any one of embodiments 1 to 55, wherein the length, in terms of the number of atoms along the shortest path counted from the atom covalently bonded to the carbonyl group (see arrow for carbonyl group) shown adjacent to to the atom covalently bonded to A, is 6 to 50. In an aspect of embodiment 70, the length is 11 to 40 atoms. In a further aspect of embodiment 70, the length is 13 to 30 atoms. In a further aspect of embodiment 70, the length is 13 to 25 atoms. In a further aspect of embodiment 70, the length is 13 to 22 atoms. In a further aspect of embodiment 70, the length is 13 to 20 atoms. In a further aspect of embodiment 70, the length is 15 to 25 atoms. In a further aspect of embodiment 70, the length is 15 to 22 atoms.

[0090] Embodiment 71: BL is of the formula [ka] and (AA) n or n is 0, then (L x ) k and (AA) in the above formula n The compound according to any one of embodiments 1 to 55, wherein the length, in terms of the number of atoms along the shortest path counted from the atom covalently bonded to the carbonyl group (see arrow for carbonyl group) shown adjacent to to the atom covalently bonded to A, is 6 to 50. In an aspect of embodiment 71, the length is 11 to 40 atoms. In a further aspect of embodiment 71, the length is 13 to 30 atoms. In a further aspect of embodiment 71, the length is 13 to 25 atoms. In a further aspect of embodiment 71, the length is 13 to 22 atoms. In a further aspect of embodiment 71, the length is 13 to 20 atoms. In a further aspect of embodiment 71, the length is 15 to 25 atoms. In a further aspect of embodiment 70, the length is 15 to 22 atoms.

[0091] Embodiment 72: The compound according to any one of embodiments 1 to 55, wherein the compound has a molecular weight of between 800 Da and 2500 Da when not radiolabeled.

[0092] Embodiment 73: The compound according to any one of embodiments 1 to 55, wherein the compound has a molecular weight of between 1000 Da and 1500 Da when not radiolabeled.

[0093] Embodiment 74: The compound according to any one of embodiments 1 to 55, wherein the compound has a molecular weight of between 1000 Da and 1300 Da when not radiolabeled.

[0094] Embodiment 75: The compound according to any one of embodiments 1 to 55, wherein the compound has a molecular weight of between 1000 Da and 1200 Da when not radiolabeled.

[0095] Embodiment 76: The compound according to any one of embodiments 1 to 55, wherein the compound has a molecular weight of between 1000 Da and 1150 Da when not radiolabeled.

[0096] Embodiment 77: The compound according to any one of embodiments 1 to 55, wherein the compound has a molecular weight of between 1100 Da and 1200 Da when not radiolabeled.

[0097] Embodiment 78: Structural Formula [ka] or a pharmaceutically acceptable salt thereof.

[0098] Embodiment 80: A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof. In some aspects of this embodiment, the cancer is ovarian cancer. In a further aspect of this embodiment, the cancer is non-small cell lung cancer.

[0099] Embodiment 81: Structural Formula [ka] or a pharmaceutically acceptable salt thereof.

[0100] Embodiment 82: Structural Formula [ka] or a pharmaceutically acceptable salt thereof.

[0101] Embodiment 83: A method for diagnosing cancer in a subject, comprising administering to the subject an effective amount of a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof.

[0102] Embodiment 84: Structural Formula [ka] or a pharmaceutically acceptable salt thereof.

[0103] Embodiment 85: A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof. In some aspects of this embodiment, the cancer is ovarian cancer. In a further aspect of this embodiment, the cancer is non-small cell lung cancer.

[0104] Embodiment 86: Structural Formula [ka] or a pharmaceutically acceptable salt thereof.

[0105] Embodiment 87: Structural Formula [ka] or a pharmaceutically acceptable salt thereof.

[0106] Embodiment 88: A method for diagnosing cancer in a subject, comprising administering to the subject an effective amount of a compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compounds of the present disclosure, when not radiolabeled, have a molecular weight of 800 Da to 4000 Da, 800 Da to 3500 Da, 800 Da to 3000 Da, 800 Da to 2500 Da, 800 Da to 2000 Da, 800 Da to 1800 Da, 800 Da to 1700 Da, 800 Da to 1600 Da, 800 Da to 1500 Da, 800 Da to 1400 Da, 800 Da to 1600 Da, 800 Da to 1800 Da, 800 Da to 1900 Da, 800 Da to 2100 Da, 800 Da to 2200 Da, 800 Da to 2300 Da, 800 Da to 2400 Da, 800 Da to 2500 Da, 800 Da to 2600 Da, 800 Da to 2700 Da, 800 Da to 2800 Da, 800 Da to 2900 Da, 800 Da to 3000 Da, 800 Da to 3100 Da, 800 Da to 3200 Da, 800 Da to 3300 Da, 800 Da to 3400 Da, 800 Da to 3500 Da, 800 Da to 3500 Da, 800 Da to 3000 Da, 800 Da to 2500 Da, 800 Da to 2000 Da, 800 Da to 2600 Da, 800 Da to 2700 Da, 800 Da to 3600 Da, 800 Da to 3700 Da, 800 Da to 3800 Da, 800 Da to 3 and a molecular weight of 1000 Da to 1300 Da, 1000 Da to 2000 Da, 1000 Da to 1800 Da, 1000 Da to 1700 Da, 1000 Da to 1600 Da, 1000 Da to 1500 Da, 1000 Da to 1400 Da, 1000 Da to 1300 Da, 1000 Da to 1200 Da, or 1000 Da to 1150 Da, or 1100 Da to 1200 Da.

[0108] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, comprise L 2 Does not contain groups.

[0109] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are selected from the group consisting of AA, L 1 and L 3 Contains only the group (L x ) k It has a group.

[0110] In another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula BL-L 3 -Ch, BL-L 1 -L 3 -Ch, BL-L 3 -L 3 -L 1 -L 1 -L 1 -L 3 -Ch, BL-L 3 -L 1 -Ch, BL-L 3 -L 3 -L 3 -Ch, BL-L 3 -L 3 -L 1 -L 3 -L 3-Ch, BL-L 3 -L 1 -L 3 -Ch, BL-L 3 -L 3 -AA-L 1 -L 2 -L 3 -Ch, BL-L 3 -L 3 -L 1 -L 1 -L 1 -L 2 -Ch, BL-L 3 -L 3 -L 3 -L 1 -AA-Ch, BL-L 3 -L 3 -AA-Ch, BL-L 3 -L 3 -Ch, BL-L 3 -L 1 -AA-Ch, BL-L 3 -L 3 -L 3 -L 1 -Ch, BL-L 3 -L 3 -L 3 -L 1 -L 1 -Ch, BL-L 3 -L 1 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch, BL-L 3 -AA-Ch, BL-L 3 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch, or BL-L 3 -L 3 -L 3 -AA-Ch, BL-L 3 -L 3 -L 3 -L 3 -Ch, where each AA is independently an amino acid residue (i.e., when two or more AA are shown in the above formula, the AA groups may all be different, all the same, or some different and some the same), and L 1 , L2 , L 3 Each of L, BL, and Ch is independently as described herein (i.e., two or more L 1 If is shown in the above formula, L 1 The groups may all be different, all the same, or some different and some the same; two or more L 3 If is shown in the above formula, L 3 The groups may all be different, all the same, or some different and some the same).

[0111] In another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula BL-L 3 -Ch, BL-L 1 -L 1 -L 1 -L 3 -Ch, BL-L 1 -Ch, BL-L 3 -L 3 -Ch, BL-L 1 -L 3 -L 3 -Ch, BL-L 1 -L 3 -Ch, BL-L 3 -L 3 -AA-L 1 -L 2 -L 3 -Ch, BL-L 1 -L 1 -L 1 -L 2 -Ch, BL-L 3 -L 3 -L 1 -AA-Ch, BL-L 3 -AA-Ch, BL-L 1 -AA-Ch, BL-L 3 -L 3 -L 1 -Ch, BL-L 3 -L 1 -Ch, BL-L 3 -L 3 -L 1 -L 1 -Ch, BL-L 3 -L 1 -L1 -Ch, BL-L 1 -L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch, BL-AA-Ch, BL-L 1 -L 1 -L 1 -AA-AA-AA-AA-Ch, or BL-L 1 -L 1 -L 1 -L 1 -L 2 -L 3 -L 1 -L 1 -Ch, and BL comprises one amino acid residue covalently bonded to a pteryl group or derivative thereof; each AA is independently an amino acid residue (i.e., when two or more AA are shown in the above formula, the AA groups may all be different, all the same, or some different and some the same), and L 1 , L 2 , L 3 Each of L, BL, and Ch is independently as described herein (i.e., two or more L 1 If is shown in the above formula, L 1 The groups may all be different, all the same, or some different and some the same; two or more L 3 When is shown by the above formula, L 3 The groups may all be different, all the same, or some different and some the same).

[0112] In another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula BL-L x -L a -L x -Ch, BL-L x -L x -L a -L x -Ch, BL-L x -L x -L a -Ch or BL-L x -L x -L a -La -Ch and L a teeth, [ka] and each L x are independently, AA, L 1 , or L 3 and AA, L 1 , L 3 , BL and Ch are as described herein, for example, with respect to embodiment 1 or 2. More specifically, L a teeth, [ka] It could be.

[0113] In another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula BL-L a -L x -Ch, BL-L x -L a -L x -Ch, BL-L x -L a -Ch or BL-L x -L a -L a -Ch and L a teeth, [ka] and each L x are independently, AA, L 1 , or L 3 and AA, L 1 , L 3 , BL and Ch are as described herein, for example, with respect to embodiment 1 or 2. More specifically, L a teeth, [ka] It could be.

[0114] In another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula BL-L x -L b -L x -Ch, BL-L x -L b -Ch or BL-L x -L b -L b -Ch and L b teeth, [ka] and each L x are independently, AA, L 1 , or L 3 and AA, L 1 , L 3 , BL and Ch are as described herein, for example, with respect to embodiment 1 or 2. More specifically, L b teeth, [ka] It could be.

[0115] In another embodiment, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, has the formula BL-L b -L x -Ch, BL-L b -Ch or BL-L b -L b -Ch and L b teeth, [ka] and each L x are independently, AA, L 1 , or L 3 and AA, L 1 , L 3 , BL and Ch are as described herein, for example, with respect to embodiment 1 or 2. More specifically, L b teeth, [ka] It could be.

[0116] In another embodiment, the compounds of the present disclosure have the formula (C1)-(C32): [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. In a particular embodiment, BL is as described in any one of embodiments 1 and 16-36, and Ch is as described in embodiment 1. In a further particular embodiment, BL is as described in any one of embodiments 1 and 16-36, and Ch is as described in embodiment 40. In a further particular embodiment, BL is as described in embodiment 16, and Ch is as described in embodiment 1 or 40. In a further particular embodiment, BL is as described in embodiment 35, and Ch is as described in embodiment 1, 39, or 40. In a further particular embodiment, BL is as described in embodiment 35, and Ch is as described in embodiment 39. In a further particular embodiment, BL is as described in embodiment 35, and Ch is as described in embodiment 40.

[0117] In another embodiment, the compound of the present disclosure is of formula (C11) (see above), wherein BL and Ch are as described herein, e.g., BL is as described in any one of embodiments 1 and 16-36, and Ch is as described in embodiment 1 or 40; or a pharmaceutically acceptable salt thereof. In a particular embodiment, BL is as described in any one of embodiments 1 and 16-36, and Ch is as described in embodiment 1. In a further particular embodiment, BL is as described in any one of embodiments 1 and 16-36, and Ch is as described in embodiment 40. In a further particular embodiment, BL is as described in embodiment 16, and Ch is as described in embodiment 1 or 40. In a further particular embodiment, BL is as described in embodiment 35, and Ch is as described in embodiment 1, 39, or 40. In a further particular embodiment, BL is as described in embodiment 35, and Ch is as described in embodiment 39. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 40.

[0118] In another embodiment, the compound of the present disclosure is of formula (C12) (see above), wherein BL and Ch are as described herein, e.g., BL is as described in any one of embodiments 1 and 16-36, and Ch is as described in embodiment 1 or 40; or a pharmaceutically acceptable salt thereof. In a particular embodiment, BL is as described in any one of embodiments 1 and 16-36, and Ch is as described in embodiment 1. In a further particular embodiment, BL is as described in any one of embodiments 1 and 16-36, and Ch is as described in embodiment 40. In a further particular embodiment, BL is as described in embodiment 16, and Ch is as described in embodiment 1 or 40. In a further particular embodiment, BL is as described in embodiment 35, and Ch is as described in embodiment 1, 39, or 40. In a further particular embodiment, BL is as described in embodiment 35, and Ch is as described in embodiment 39. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 40.

[0119] In another embodiment, the compounds of the present disclosure have the formula (C1)-(C32): [ka] [ka] [ka] [ka] [ka] (wherein L as defined in embodiment 1 in any one of the above formulae (C1) to (C32) x (i.e., AA, L 1 , L 2 , or L 3 ) is a group corresponding to a different L as defined in embodiment 1 x and BL and Ch are as described herein, e.g., BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 1 or 40; or a pharmaceutically acceptable salt thereof. In a particular embodiment, BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 1. In a further particular embodiment, BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 40. In a further particular embodiment, BL is as described in embodiment 16 and Ch is as described in embodiment 1 or 40. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 1, 39 or 40. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 39. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 40. In a further particular embodiment, different L x One group replaced by a different L is an AA group. x are different AA groups, and the different AA groups are conservative amino acid substitutions for the AA groups (e.g., this means that this embodiment encompasses compounds in which, for example, one aspartic acid residue (e.g., in formula (C11)) is replaced by a different AA, and this replacement is a conservative amino acid substitution).

[0120] In another embodiment, the compounds of the present disclosure are of formula (C11) (see above) (wherein L is as defined in embodiment 1 of any one of the foregoing formulae (C1) to (C32)). x (i.e., AA, L 1 , L 2 , or L 3 ) is a group corresponding to a different L as defined in embodiment 1 x and BL and Ch are as described herein, e.g., BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 1 or 40; or a pharmaceutically acceptable salt thereof. In a particular embodiment, BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 1. In a further particular embodiment, BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 40. In a further particular embodiment, BL is as described in embodiment 16 and Ch is as described in embodiment 1 or 40. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 1, 39 or 40. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 39. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 40. In a further particular embodiment, different L x One group replaced by a different L is an AA group. x are different AA groups, and the different AA groups are conservative amino acid substitutions for the AA groups (e.g., this means that this embodiment encompasses compounds in which, for example, one aspartic acid residue (e.g., in formula (C11)) is replaced by a different AA, and this replacement is a conservative amino acid substitution).

[0121] In another embodiment, the compounds of the present disclosure are of formula (C12) (see above) (wherein L is as defined in embodiment 1 of any one of the foregoing formulae (C1) to (C32)). x (i.e., AA, L 1 , L 2 , or L 3 ) is a group corresponding to a different L as defined in embodiment 1 x and BL and Ch are as described herein, e.g., BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 1 or 40; or a pharmaceutically acceptable salt thereof. In a particular embodiment, BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 1. In a further particular embodiment, BL is as described in any one of embodiments 1 and 16-36 and Ch is as described in embodiment 40. In a further particular embodiment, BL is as described in embodiment 16 and Ch is as described in embodiment 1 or 40. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 1, 39 or 40. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 39. In a further particular embodiment, BL is as described in embodiment 35 and Ch is as described in embodiment 40. In a further particular embodiment, different L x One group replaced by a different L is an AA group. x are different AA groups, and the different AA groups are conservative amino acid substitutions for the AA groups (e.g., this means that this embodiment encompasses compounds in which, for example, one aspartic acid residue (e.g., in formula (C11)) is replaced by a different AA, and this replacement is a conservative amino acid substitution).

[0122] In a further embodiment, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof; the chelating group shown in the above structural formula is selected from the group consisting of a radioactive element, Si- 18 F, B- 18 F or Al- 18 In certain embodiments, the chelating group represented by the structural formula above does not contain a radioactive element (i.e., the compound is a non-radioactive compound). In certain alternative embodiments, the chelating group represented by the structural formula above does not contain a radioactive element, Si- 18 F, B- 18 F or Al- 18 Contains F (i.e., the compound is a radioactive compound).

[0123] Another embodiment is a compound of formula (IV), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, each L x is independently, L1 , L 3 Or AA and BL, A, L 1 , L 3 , A.A., R. 16 , R 38 , and R 39 is as defined herein, e.g., as defined in embodiment 1 or 2; k1 is 1, 2, 3, 4, 5, 6, or 7; k2 is 1, 2, 3, 4, 5, 6, or 7; and k1 + k2 does not exceed 8. In certain embodiments, R 16 , R 37 and R 38 is H; and R 39 In further particular embodiments of the foregoing or particular embodiments, each L 1 (if present) independently, the formula [ka] (In the formula, R 16 is H, Each R 17 and R 17’ are independently H, C1-C6 alkyl, or —C(O)OH; Each R 18 are independently H, C6 to C 10 Aryl, -OH-SH, -NHC(=NH ’ )NH2 or -C(O)OH, C6 to C 10 each hydrogen atom in the aryl is independently optionally replaced by a halogen; Each L 3 (if present) independently represents -C(O)C3-C6 cycloalkylene-(CH2) r NH-, -(CR 39 R 39’ ) r C(O)-, -C(O)(CR 39 R 39’ ) r -, -NH(CR 39 R 39’ ) r -, -(CR 39 R39’ ) r NH-、-NH(CR 39 R 39’ ) r NH-、-NH(CH2CH2O) rp -(CR 36 R 36’ ) t C(O)-、-C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NH-、-C(O)(CR 36 R 36’ ) r -O-(C6~C 10 アリール)-(CR 36’’ R 36’’’ ) t NH-、-NH(CR 36 R 36’ ) r -(C6~C 10 アリール)-O-(CR 36’’ R 36’’’ ) t C(O)-、-C(O)-(CR 36 R 36’ ) r -NH-C(O)-(C6~C 10 アリール)-NH-、-NR 37 -(C6~C 10 アリール)-C(O)-NH-(CR 36 R 36’ ) r -C(O)-、-NH(CR 36 R 36’ ) r -(C6~C 10 アリール)-O-(CR 36’’ R 36’’’ ) t -、-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 アリール)-(CR 36 R 36’ ) r -NH-、-NH(CR 36 R 36’ )r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NH- or -NH-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-; and AA (if present) is an amino acid residue; Each R 36 , R 36’ , R 36’’ , R 36’’’ , R 39 and R 39’ are independently H or —COOH; each r is independently 1, 2, 3, 4, or 5; and each t is independently 1, 2, 3, 4, or 5).

[0124] Another embodiment is a compound of formula (V), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, each L x is independently, L 1 , L 3 or AA; and BL, Ch, L 1 , L 3 and AA are as defined herein, e.g., as defined in embodiment 1 or 2; k1 is 1, 2, 3, 4, 5, 6, or 7; k2 is 1, 2, 3, 4, 5, 6, or 7; and k1 + k2 does not exceed 8). In certain embodiments, R 16 , R 37 and R 38 is H; and R 39 In further particular embodiments of the foregoing or particular embodiments, each L 1 (if present) independently, the formula [ka] (In the formula, R 16 is H, Each R 17 and R 17’ are independently H, C1-C6 alkyl, or —C(O)OH; Each R 18 are independently H, C6 to C 10 Aryl, -OH-SH, -NHC(=NH ’ )NH2 or -C(O)OH, C6 to C 10 each hydrogen atom in the aryl is independently optionally replaced by a halogen; Each L 3 (if present) independently represents -C(O)C3-C6 cycloalkylene-(CH2) r NH-, -(CR 39 R 39’ ) r C(O)-, -C(O)(CR 39 R 39’ ) r -, -NH(CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r NH-, -NH(CR 39 R 39’ ) r NH-, -NH(CH2CH2O) rp -(CR 36 R 36’ ) t C(O)-, -C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NH-, -C(O)(CR 36 R 36’ ) r -O-(C6~C 10 Aryl)-(CR 36’’ R 36’’’ ) t NH-, -NH(CR 36R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t C(O)-, -C(O)-(CR 36 R 36’ ) r -NH-C(O)-(C6~C 10 Aryl)-NH-, -NR 37 -(C6~C 10 aryl)-C(O)-NH-(CR 36 R 36’ ) r -C(O)-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NH- or -NH-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-; and AA (if present) is an amino acid residue; Each R 36 , R 36’ , R 36’’ , R 36’’’ , R 39 and R 39’ are independently H or —COOH; each r is independently 1, 2, 3, 4, or 5; and each t is independently 1, 2, 3, 4, or 5).

[0125] Another embodiment is a compound of formula (VI), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, each L x is independently, L 1 , L 3 or AA; and BL, Ch, L 1 , L 3 and AA are independently as defined herein, e.g., as defined in embodiment 1 or 2; k1 is 1, 2, 3, 4, 5, or t; k2 is 1, 2, 3, 4, 5, or 6; and k1 + k2 does not exceed 8. In certain of the foregoing embodiments, each L 1 (if present) independently, the formula [ka] (In the formula, R 16 is H, Each R 17 and R 17’ are independently H, C1-C6 alkyl, or —C(O)OH; Each R 18 are independently H, C6 to C 10 Aryl, -OH-SH, -NHC(=NH ’ )NH2 or -C(O)OH, C6 to C 10 each hydrogen atom in the aryl is independently optionally replaced by a halogen; Each L 3 (if present) independently represents -C(O)C3-C6 cycloalkylene-(CH2) r NH-, -(CR 39 R 39’ ) r C(O)-, -C(O)(CR 39 R 39’ ) r -, -NH(CR39 R 39’ ) r -、-(CR 39 R 39’ ) r NH-、-NH(CR 39 R 39’ ) r NH-、-NH(CH2CH2O) rp -(CR 36 R 36’ ) t C(O)-、-C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NH-、-C(O)(CR 36 R 36’ ) r -O-(C6~C 10 アリール)-(CR 36’’ R 36’’’ ) t NH-、-NH(CR 36 R 36’ ) r -(C6~C 10 アリール)-O-(CR 36’’ R 36’’’ ) t C(O)-、-C(O)-(CR 36 R 36’ ) r -NH-C(O)-(C6~C 10 アリール)-NH-、-NR 37 -(C6~C 10 アリール)-C(O)-NH-(CR 36 R 36’ ) r -C(O)-、-NH(CR 36 R 36’ ) r -(C6~C 10 アリール)-O-(CR 36’’ R 36’’’ ) t -、-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 アリール)-(CR 36 R 36’) r -NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NH- or -NH-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-; and AA (if present) is an amino acid residue; Each R 36 , R 36’ , R 36’’ , R 36’’’ , R 39 and R 39’ are independently H or —COOH; each r is independently 1, 2, 3, 4, or 5; and each t is independently 1, 2, 3, 4, or 5).

[0126] Another embodiment is a compound of formula (VI), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, each L x are independently AA; BL is a folate receptor binding ligand, and Ch is a metal, radioactive element, Si- 18 F, B- 18 F or Al- 18 F; k1 is 1, 2, 3, 4, 5, or t; k2 is 1, 2, 3, 4, 5, or 6; and k1 + k2 does not exceed 8). In certain embodiments, Ch is [ka] is.

[0127] In some embodiments, the compound is not a compound of formula (E1)-(E2) (as described herein), a tautomer of (E1)-(E5), a compound of (E1)-(E5) to which a metal or radioactive element is chelated, or a pharmaceutical salt of (E1)-(E5).

[0128] Folate receptor binding ligand (BL) The compounds of the present disclosure (also referred to as FR-targeting / targeting compounds), such as compounds of formula (I), or pharmaceutically acceptable salts thereof, comprise a folate receptor binding ligand (BL). Typically, the BL can bind to all functional folate receptor isoforms, including, but not limited to, FR-α, FR-β, and FR-γ.

[0129] In some embodiments, the BL binds to FR-α, which is expressed or overexpressed in many cancers.

[0130] In some embodiments, the BL binds to FR-β.

[0131] In some embodiments, the BL binds to FR-γ.

[0132] In some embodiments, the BL binds to FR-α and FR-β.

[0133] In some embodiments, the BL binds to FR-α, FR-β, and FR-γ.

[0134] In some embodiments, BL is folic acid, or a derivative, fragment, or free base thereof.

[0135] In some embodiments, BL is a pteryl group or a derivative thereof (ie, pteroic acid or a derivative thereof in which the carboxyl group has been reacted with the amino group, typically of an amino acid).

[0136] In some embodiments, BL is a group represented by formula (IIa): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R1', R 2’ , X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , m, n, AA and * are as defined in any one of embodiments 17 to 34).

[0137] In some embodiments, BL is a group represented by formula (IIb): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , Y 1 , Y 2 , m, and * are as defined in any one of embodiments 17 to 34).

[0138] In some embodiments, BL is a group represented by formula (IIc): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4, X 5 , Y 1 , Y 2 , m, and * are as defined in any one of embodiments 17 to 34).

[0139] In some embodiments, BL is of the formula [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , X 1 , X 2 , X 3 , X 4 , X 5 , m and * are as defined in any one of embodiments 17 to 34).

[0140] In some embodiments, BL is of the formula [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y 1 , Y 2 , X 1 , X 2 , X 3 , X 4 , X 5 , m and * are as defined in any one of embodiments 17 to 34).

[0141] In some embodiments described herein, R 1 and R 2is H. In some embodiments described herein, m is 1. In some embodiments described herein, R 3 is H. In some embodiments described herein, R 4 is H. In some embodiments described herein, R 5 is H. In some embodiments described herein, R 6 is H. In some embodiments described herein, R 3 , R 4 , R 5 and R 6 is H. In some embodiments described herein, X 1 is -NR 11 and R 11 is H. In some embodiments described herein, X 2 is ═N—. In some embodiments described herein, X 3 In some embodiments described herein, X 4 In some embodiments described herein, X 1 is -NR 11 and R 11 is H;X 2 is =N-;X 3 is -N =; and X 4 In some embodiments described herein, X 5 is NR 12 and R 12 is H. In some embodiments, Y 1 is ═O. In some embodiments, Y 2 does not exist.

[0142] In some embodiments, BL is of the formula [ka] where * is a covalent bond to the remainder of the compound.

[0143] In some embodiments, BL is of the formula [ka] where * is a covalent bond to the remainder of the compound.

[0144] In some embodiments, BL is of the formula [ka] where * is a covalent bond to the remainder of the compound.

[0145] In some embodiments, BL is of the formula [ka] where * is a covalent bond to the remainder of the compound.

[0146] In some embodiments, BL is of the formula [ka] where * is a covalent bond to the remainder of the compound.

[0147] In some embodiments, BL comprises a pteryl group or a derivative thereof, wherein the pteryl group or a derivative thereof is [ka] is covalently bonded to a group selected from

[0148] Linker (L x ) k Linker (L x ) kconnects BL to A in the compounds described herein. It is the covalently linked k group L x This covalent linkage can be achieved, for example, by x The carboxyl group of the precursor and the other L x It may be the result of a condensation reaction between the amino groups of the precursors. x ) k Each L x are independently AA, L as defined herein. 1 , L 2 and L 3 may be selected from:

[0149] In some embodiments, the compound of formula (I) is (L x ) k Each L x are independently AA, L as defined herein. 1 , L 2 and L 3 and k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; x ) k Includes:

[0150] In some embodiments, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, k is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, k is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, k is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, k is 1, 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, 4, or 5. In some embodiments, k is 1, 2, 3, or 4.

[0151] AA is an amino acid residue as defined herein. In certain embodiments, AA is a naturally occurring amino acid residue. In certain embodiments, AA exists in the L-form. In certain embodiments, AA exists in the D-form. In certain embodiments, the compounds described herein will comprise two or more amino acids as part of the linker, and it will be understood that the amino acid residues may be the same or different and may be selected from a group of amino acid residues. In certain embodiments, the compounds described herein will comprise two or more amino acid residues as part of the linker, and it will be understood that the amino acid residues may be the same or different and may be selected from a group of amino acid residues in the D- or L-form. In some embodiments, AA can be covalently linked to BL, another linker moiety, or A through the alpha-amino group of the amino acid corresponding to AA. In some embodiments, AA can be covalently linked to BL, another linker moiety, or A through the carboxyl group of the amino acid corresponding to AA. In some embodiments, AA can be covalently linked to BL, another linker moiety, or A through the side chain group of the amino acid corresponding to AA. In some embodiments, AA can be covalently linked to BL, another linker moiety, or A via a combination of the alpha-amino group of the amino acid corresponding to AA, the carboxyl group of the amino acid corresponding to AA, or the side chain of the amino acid corresponding to AA.

[0152] In some embodiments, each AA is independently selected from the group consisting of L-lysine, L-glycine, L-aspartic acid, L-glutamic acid, L-glutamine, L-cysteine, L-alanine, L-valine, L-leucine, L-isoleucine, L-3-amino-alanine, L-arginine, D-lysine, D-glycine, D-aspartic acid, D-glutamic acid, D-glutamine, D-cysteine, D-alanine, D-valine, D-leucine, D-isoleucine, D-3-amino-alanine, and D-arginine. In some embodiments, each AA is independently selected from the group consisting of L-3-amino-alanine, Lys, Asp, Arg, Glu, and Cys.

[0153] In the compounds described herein, e.g., compounds of formula (I), or pharmaceutically acceptable salts thereof, one or more L 1 may be present, and L 1 In some embodiments, each L 1 is, independently, [ka] (In the formula, R 16 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)R 19 , -C(O)OR 19 and -C(O)NR 19 R 19’ and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, -OR 20 , -OC(O)R 20 , -OC(O)NR 20 R 20’ , -OS(O)R 20 , -OS(O)2R 20 , -SR 20 , -S(O)R 20 , -S(O)2R 20 , -S(O)NR 20 R 20’ , -S(O)NR 20 R 20’ , -OS(O)NR 20 R 20’ , -OS(O)2NR 20 R 20’ , -NR 20 R 20’ , -NR 20 C(O)R 21 , -NR 20 C(O)OR 21 , -NR 20 C(O)NR 21 R 21’ , -NR 20 S(O)R 21 , -NR 20 S(O)2R21 , -NR 20 S(O)NR 21 R 21’ , -NR 20 S(O)NR 21 R 21’ , -C(O)R 20 , -C(O)OR 20 or -C(O)NR 20 R 20’ independently and optionally replaced by; Each R 17 and R 17’ are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 22 , -OC(O)R 22 , -OC(O)NR 22 R 22’ , -OS(O)R 22 , -OS(O)2R 22 , -SR 22 , -S(O)R 22 , -S(O)2R 22 , -S(O)NR 22 R 22’ , -S(O)NR 22 R 22’ , -OS(O)NR 22 R 22’ , -OS(O)2NR 22 R 22’ , -NR 22 R 22’ , -NR 22 C(O)R 23 , -NR 22 C(O)OR 23 , -NR 22 C(O)NR 23 R 23’ , -NR 22 S(O)R 23 , -NR 22 S(O)2R 23 , -NR 22 S(O)NR 23 R 23’ , -NR 22 S(O)NR 23 R 23’, -C(O)R 22 , -C(O)OR 22 , and -C(O)NR 22 R 22’ and selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 7-membered heteroaryl can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR 24 , -OC(O)R 24 , -OC(O)NR 24 R 24’ , -OS(O)R 24 , -OS(O)2R 24 , -SR 24 , -S(O)R 24 , -S(O)2R 24 , -S(O)NR 24 R 24’ , -S(O)NR 24 R 24’ , -OS(O)NR 24 R 24’ , -OS(O)2NR 24 R 24’ , -NR 24 R 24’ , -NR 24 C(O)R 25 , -NR 24 C(O)OR 25 , -NR 24 C(O)NR 25 R 25’ , -NR 24 S(O)R 25 , -NR 24 S(O)2R 25 , -NR 24 S(O)NR 25 R 25’ , -NR 24 S(O)NR 25 R 25’ , -C(O)R 24 , -C(O)OR 24 or -C(O)NR 24 R 24’ or R 17 and R 17’may be combined to form a C4-C6 cycloalkyl or a 4- to 6-membered heterocycle, and each hydrogen atom in the C4-C6 cycloalkyl or the 4- to 6-membered heterocycle may be replaced by a halogen, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C3-C6 cycloalkyl, a 3- to 7-membered heterocycloalkyl, a C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 24 , -OC(O)R 24 , -OC(O)NR 24 R 24’ , -OS(O)R 24 , -OS(O)2R 24 , -SR 24 , -S(O)R 24 , -S(O)2R 24 , -S(O)NR 24 R 24’ , -S(O)NR 24 R 24’ , -OS(O)NR 24 R 24’ , -OS(O)2NR 24 R 24’ , -NR 24 R 24’ , -NR 24 C(O)R 25 , -NR 24 C(O)OR 25 , -NR 24 C(O)NR 25 R 25’ , -NR 24 S(O)R 25 , -NR 24 S(O)2R 25 , -NR 24 S(O)NR 25 R 25’ , -NR 24 S(O)NR 25 R 25’ , -C(O)R 24 , -C(O)OR 24 or -C(O)NR 24 R 24’ independently and optionally replaced by; R 18 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 Aryl, 5- to 7-membered heteroaryl, -OR 26 , -OC(O)R 26 , -OC(O)NR 26 R 26’ , -OS(O)R 26 , -OS(O)2R 26 , -SR 26 , -S(O)R 26 , -S(O)2R 26 , -S(O)NR 26 R 26’ , -S(O)NR 26 R 26’ , -OS(O)NR 26 R 26’ , -OS(O)2NR 26 R 26’ , -NR 26 R 26’ , -NR 26 C(O)R 27 , -NR 26 C(O)OR 27 , -NR 26 C(O)NR 27 R 27’ , -NR 26 C(=NR 26’’ )NR 27 R 27’ , -NR 26 S(O)R 27 , -NR 26 S(O)2R 27 , -NR 26 S(O)NR 27 R 27’ , -NR 26 S(O)NR 27 R 27’ , -C(O)R 26 , -C(O)OR 26 and -C(O)NR 26 R 26’ and selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 7-membered heteroaryl can be replaced by a halogen, a C1-C6 alkyl, a C2-C6 alkenyl, -(CH2) p OR 28 , -(CH2)p (OCH2) q OR 28 , -(CH2) p (OCH2CH2) q OR 28 , -OR 29 , -OC(O)R 29 , -OC(O)NR 29 R 29’ , -OS(O)R 29 , -OS(O)2R 29 , -(CH2) p OS(O)2OR 29 , -OS(O)2OR 29 , -SR 29 , -S(O)R 29 , -S(O)2R 29 , -S(O)NR 29 R 29’ , -S(O)NR 29 R 29’ , -OS(O)NR 29 R 29’ , -OS(O)2NR 29 R 29’ , -NR 29 R 29’ , -NR 29 C(O)R 30 , -NR 29 C(O)OR 30 , -NR 29 C(O)NR 30 R 30’ , -NR 29 S(O)R 30 , -NR 29 S(O)2R 30 , -NR 29 S(O)NR 30 R 30’ , -NR 29 S(O)NR 30 R 30’ , -C(O)R 29 , -C(O)OR 29 or -C(O)NR 29 R 29’ independently and optionally replaced by; Each R 19 , R 19’ , R 20 , R 20’ , R 21 , R21’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ are independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl and 5- to 7-membered heteroaryl, and is selected from the group consisting of C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 each hydrogen atom in the aryl or 5- to 7-membered heteroaryl is independently optionally replaced with halogen, —OH, —SH, —NH2, or —CO2H; R 27 and R 27’ are each independently H, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C3-C6 cycloalkyl, -(CH2) p (sugar), -(CH2) p (OCH2CH2) q -(sugar) and -(CH2) p (OCH2CH2CH2) q (sugars); R 28 is H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5-7 membered heteroaryl, or sugar; w is 1, 2, 3, 4 or 5; p is 1, 2, 3, 4 or 5; q is 1, 2, 3, 4 or 5; Each * represents a covalent bond.

[0154] L 1 It will be understood that when written in accordance with the above formula, both R and S configurations are contemplated.

[0155] In some embodiments, each L 1 is, independently, [ka] is selected from the group consisting of R 16 are defined as described herein, and each * represents a covalent bond to the remainder of the compound.

[0156] In some embodiments, R 16 is H. In some embodiments, R 18 is H, 5- to 7-membered heteroaryl, -OR 26 , -NR 26 C(O)R 27 , -NR 26 C(O)NR 27 R 27’ , -NR 26 C(=NR 26’’ )NR 27 R 27’ , and -C(O)NR 26 R 26’ Each hydrogen atom of the 5- to 7-membered heteroaryl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, -(CH2) p OR 28 , -(CH2) p (OCH2) q OR 28 , -(CH2) p (OCH2CH2) q OR 28 , -OR 29 , -OC(O)R 29 , -OC(O)NR 29 R 29’ , -OS(O)R 29 , -OS(O)2R 29 , -(CH2) p OS(O)2OR 29, -OS(O)2OR 29 , -SR 29 , -S(O)R 29 , -S(O)2R 29 , -S(O)NR 29 R 29’ , -S(O)NR 29 R 29’ , -OS(O)NR 29 R 29’ , -OS(O)2NR 29 R 29’ , -NR 29 R 29’ , -NR 29 C(O)R 30 , -NR 29 C(O)OR 30 , -NR 29 C(O)NR 30 R 30’ , -NR 29 S(O)R 30 , -NR 29 S(O)2R 30 , -NR 29 S(O)NR 30 R 30’ , -NR 29 S(O)NR 30 R 30’ , -C(O)R 29 , -C(O)OR 29 or -C(O)NR 29 R 29’ independently and optionally replaced by; Each R 26 , R 26’ , R 26’’ , R 29 , R 29’ , R 30 and R 30’ are independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl and 5- to 7-membered heteroaryl, and is selected from the group consisting of C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10each hydrogen atom in the aryl or 5- to 7-membered heteroaryl is independently optionally replaced with halogen, —OH, —SH, —NH2, or —CO2H; R 27 and R 27’ are each independently H, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, C3-C6 cycloalkyl, -(CH2) p (sugar), -(CH2) p (OCH2CH2) q -(sugar) and -(CH2) p (OCH2CH2CH2) q (sugars); R 28 is H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5- to 7-membered heteroaryl, or sugar; w is 1, 2, 3, 4 or 5; p is 1, 2, 3, 4 or 5; q is 1, 2, 3, 4 or 5; and Each * represents a covalent bond to the remainder of the compound.

[0157] In some embodiments, R 18 are independently H, C6 to C 10 Aryl, -OH-SH, -NHC(=NH ’ )NH2 or -C(O)OH, C6 to C 10 Each hydrogen atom in the aryl is independently optionally replaced by a halogen.

[0158] In some embodiments, the compounds described herein include L 1 Contains R 17 and R 17’ is H and R 18 is a 5- to 7-membered heteroaryl. In some embodiments, the compounds described herein include 1 Contains R 17 and R 17’ is H and R18 is 2-naphthyl.

[0159] In some embodiments of the conjugates described herein, L 1 In some embodiments of the conjugates described herein, L 1 is absent. In some embodiments, z2 is 0. In some embodiments, z2 is 1. In some embodiments, z2 is 2. In some embodiments, z2 is 3.

[0160] In the compounds described herein, one or more L 2 may be present, and L 2 may not be present.

[0161] In some embodiments, each L 2 is the expression [ka] (In the formula, respectively or R 31 and R 31’ are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 32 , -OC(O)R 32 , -OC(O)NR 32 R 32’ , -OS(O)R 32 , -OS(O)2R 32 , -SR 32 , -S(O)R 32 , -S(O)2R 32 , -S(O)NR 32 R 32’ , -S(O)NR32 R 32’ , -OS(O)NR 32 R 32’ , -OS(O)2NR 32 R 32’ , -NR 32 R 32’ , -NR 32 C(O)R 33 , -NR 32 C(O)OR 33 , -NR 32 C(O)NR 33 R 33’ , -NR 32 S(O)R 33 , -NR 32 S(O)2R 33 , -NR 32 S(O)NR 33 R 33’ , -NR 32 S(O)NR 33 R 33’ , -C(O)R 32 , -C(O)OR 32 or -C(O)NR 32 R 32’ independently and optionally replaced by; X 6 is C1 to C6 alkyl or C6 to C 10 Aryl (C1-C6 alkyl), C1-C6 alkyl and C6-C 10 Each hydrogen atom in aryl(C1-C6 alkyl) can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 34 , -OC(O)R 34 , -OC(O)NR 34 R 34’ , -OS(O)R 34 , -OS(O)2R 34 , -SR 34 , -S(O)R 34 , -S(O)2R 34 , -S(O)NR 34 R 34’ , -S(O)NR 34 R 34’ , -OS(O)NR34 R 34’ , -OS(O)2NR 34 R 34’ , -NR 34 R 34’ , -NR 34 C(O)R 35 , -NR 34 C(O)OR 35 , -NR 34 C(O)NR 35 R 35’ , -NR 34 S(O)R 35 , -NR 34 S(O)2R 35 , -NR 34 S(O)NR 35 R 35’ , -NR 34 S(O)NR 35 R 35’ , -C(O)R 34 , -C(O)OR 34 or -C(O)NR 34 R 34’ independently and optionally replaced by; Each R 32 , R 32’ , R 33 , R 33’ , R 34 , R 34’ , R 35 and R 35’ are independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl, and 5- to 7-membered heteroaryl; R 36 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37, -OC(O)R 37 , -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR 37 , -S(O)R 37 , -S(O)2R 37 , -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; R 37 , R 37’ , R 38 and R 38’ are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl and 5- to 7-membered heteroaryl; and Each * represents a covalent bond to the remainder of the compound.

[0162] In some embodiments, R 31 is H. In some embodiments, R 36 is H. In some embodiments, X 6 is C1-C6 alkyl. In some embodiments, X 6 is C1 to C6 alkyl or C6 to C 10 It is aryl-(C1-C6 alkyl).

[0163] In some embodiments, each L 2 are independently expressed as [ka] (In the formula, R 31 and R 31’ is H, R 36 is H; and Each * represents a covalent bond to the remainder of the compound.

[0164] In the compounds described herein, one or more L 3 may be present, and L 3 may not be present.

[0165] In some embodiments, each L 3 are independently C1-C6 alkylene, -OC1-C6 alkylene, -SC1-C6 alkylene, C3-C6 cycloalkylene, -C(O)C3-C6 cycloalkylene-, -C(O)C3-C6 cycloalkylene-(CR 39 R 39’ ) r -, -C(O)C3-C6 cycloalkylene-(CR 39 R 39’ ) r NR 37 -, 3-7 membered heterocycloalkylene, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -NR 36 (CR 36’ R 36’’ ) r-S-(サクシニミド-1-イル)-、-(CR 36’ R 36’’ ) r C(O)NR 37 -、-(CR 39 R 39’ ) r C(O)-、-(CR 39 R 39’ ) r OC(O)-、-S(CR 39 R 39’ ) r OC(O)-、-C(O)(CR 39 R 39’ ) r -、-C(O)O(CR 39 R 39’ ) r -、-NR 37 C(O)(CR 39 R 39’ ) r -、-(CR 39 R 39’ ) r C(O)NR 37 -、-NR 37 C(O)(CR 39’ R 39’’ ) r S-、-NR 37 (CR 39 R 39’ ) r -、-(CR 39 R 39’ ) r NR 38 -、-NR 37 (CR 39 R 39’ ) r NR 38 -、-NR 37 (CR 39 R 39’ ) r S-、-NR 37 (CR 39 R 39’ CR 39 R 39’ O) r -、-NR 37 (CR 39 R 39’ CR 39 R 39’ O) rp -(CR36 R 36’ ) t C(O)-、-C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NR 37 -、-(CR 39 R 39’ CR 39 R 39’ O) r -(CR 36 R 36’ ) t C(O)-、-C(O)(CR 36 R 36’ ) t (OCR 39 R 39’ CR 39 R 39’ CR 39 R 39’ ) r -、-C(O)(CR 36 R 36’ ) t (OCR 39 R 39’ CR 39 R 39’ CR 39 R 39’ ) r NR 37 -、-C(O)(CR 36 R 36’ ) r -O-(C6~C 10 アリール)-(CR 36’’ R 36’’’ ) t NR 37 -、-NR 37 (CR 36 R 36’ ) r -(C6~C 10 アリール)-O-(CR 36’’ R 36’’’ ) t C(O)-、-C(O)-(CR 36 R 36’ ) r -NR 37 -C(O)-(C6~C 10(aryl)-NR 37’ -, -NR 37 -(C6~C 10 Aryl)-C(O)-NR 37’ -(CR 36 R 36’ ) r -C(O)-, -NR 37 (CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NR 37 -, -NR 37 (CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NR 37’ - or -NR 37’ -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NR 37 - and C6~C 10 Each hydrogen atom in the aryl can be replaced by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37 , -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR 37 , -S(O)R 37 , -S(O)2R37 , -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; During the ceremony, Each R 36 , R 36’ , R 36’’ and R 36’’’ are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C(O)R 37 , -C(O)OR 37 and -C(O)NR 37 R 37’ and each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 37 , -OC(O)R 37, -OC(O)NR 37 R 37’ , -OS(O)R 37 , -OS(O)2R 37 , -SR 37 , -S(O)R 37 , -S(O)2R 37 , -S(O)NR 37 R 37’ , -S(O)NR 37 R 37’ , -OS(O)NR 37 R 37’ , -OS(O)2NR 37 R 37’ , -NR 37 R 37’ , -NR 37 C(O)R 38 , -NR 37 C(O)OR 38 , -NR 37 C(O)NR 38 R 38’ , -NR 37 S(O)R 38 , -NR 37 S(O)2R 38 , -NR 37 S(O)NR 38 R 38’ , -NR 37 S(O)NR 38 R 38’ , -C(O)R 37 , -C(O)OR 37 or -C(O)NR 37 R 37’ independently and optionally replaced by; R 37 , R 37’ , R 38 and R 38’ are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl and 5- to 7-membered heteroaryl; Each R 39 and R 39’are independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, 5- to 7-membered heteroaryl, -OR 40 , -OC(O)R 40 , -OC(O)NR 40 R 40’ , -OS(O)R 40 , -OS(O)2R 40 , -SR 40 , -S(O)R 40 , -S(O)2R 40 , -S(O)NR 40 R 40’ , -S(O)NR 40 R 40’ , -OS(O)NR 40 R 40’ , -OS(O)2NR 40 R 40’ , -NR 40 R 40’ , -NR 40 C(O)R 41 , -NR 40 C(O)OR 41 , -NR 40 C(O)NR 41 R 41’ , -NR 40 S(O)R 41 , -NR 40 S(O)2R 41 , -NR 40 S(O)NR 41 R 41’ , -NR 40 S(O)NR 41 R 41’ , -C(O)R 40 , -C(O)OR 40 and -C(O)NR 40 R 40’ selected from the group consisting of: R 40 , R 40’ , R 41 and R 41’ are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10selected from the group consisting of aryl and 5- to 7-membered heteroaryl; each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each rp is independently an integer from 1 to 80; each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each * represents a covalent bond.

[0166] In some embodiments, each L 3 are independently -C(O)C3-C6 cycloalkylene-(CH2) r NH-, -(CR 39 R 39’ ) r C(O)-, -C(O)(CR 39 R 39’ ) r -, -NH(CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r NH-, -NH(CR 39 R 39’ ) r NH-, -NH(CH2CH2O) rp -(CR 36 R 36’ ) t C(O)-, -C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NH-, -C(O)(CR 36 R 36’ ) r -O-(C6~C 10 Aryl)-(CR 36’’ R 36’’’ ) t NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) tC(O)-, -C(O)-(CR 36 R 36’ ) r -NH-C(O)-(C6~C 10 Aryl)-NH-, -NR 37 -(C6~C 10 aryl)-C(O)-NH-(CR 36 R 36’ ) r -C(O)-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NH- or -NH-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-; During the ceremony, Each R 36 , R 36’ , R 36’’ , R 36’’’ , R 39 and R 39’ are independently H or —COOH; each r is independently 1, 2, 3, 4, or 5; and Each t is independently 1, 2, 3, 4, or 5.

[0167] In some embodiments, each R 39’ When present, it is H. In some embodiments, one R39 When present, it is not H. In some embodiments, one R 39 If present, -OC(O)R 40 In some embodiments, R 40 is H. In some embodiments, R 38 When present, R is H. In some embodiments, R 37 When present, R is H. In some embodiments, R 36’ When present, R is H. In some embodiments, R 36 is H, if present.

[0168] In some embodiments, L 3 are independently -C(O)C3-C6 cycloalkylene-(CH2) r NH-, -(CR 39 R 39’ ) r C(O)-, -C(O)(CR 39 R 39’ ) r -, -NH(CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r NH-, -NH(CR 39 R 39’ ) r NH-, -NH(CH2CH2O) rp -(CR 36 R 36’ ) t C(O)-, -C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NH-, -C(O)(CR 36 R 36’ ) r -O-(C6~C 10 Aryl)-(CR 36’’ R 36’’’ ) t NH-, -NH(CR 36 R36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t C(O)-, -C(O)-(CR 36 R 36’ ) r -NH-C(O)-(C6~C 10 Aryl)-NH-, -NR 37 -(C6~C 10 aryl)-C(O)-NH-(CR 36 R 36’ ) r -C(O)-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NH- or -NH-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-; During the ceremony, Each R 36 , R 36’ , R 36’’ , R 36’’’ , R 39 and R 39’ are independently H or —COOH; each r is independently 1, 2, 3, 4, or 5; and Each t is independently 1, 2, 3, 4, or 5.

[0169] In some embodiments, each L 3 are independently -C(O)C3-C6 cycloalkylene-(CH2) r NH-, -(CR 39 R 39’ ) r C(O)-, -C(O)(CR 39 R 39’ ) r -, -NH(CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r NH-, -NH(CR 39 R 39’ ) r NH-, -NH(CH2CH2O) rp -(CR 36 R 36’ ) t C(O)-, -C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp -NH-, -C(O)(CR 36 R 36’ ) r -O-(C6~C 10 Aryl)-(CR 36’’ R 36’’’ ) t NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t C(O)-, -C(O)-(CR 36 R 36’ ) r -NH-C(O)-(C6~C 10 Aryl)-NH-, -NR 37 -(C6~C 10 aryl)-C(O)-NH-(CR 36 R 36’ ) r-C(O)-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NH- or -NH-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-; During the ceremony, Each R 36 , R 36’ , R 36’’ , R 36’’’ , R 39 and R 39’ are independently H or —COOH; each r is independently 1, 2, 3, 4, or 5; and Each t is independently 1, 2, 3, 4, or 5.

[0170] In some embodiments, L 3 is present. In some embodiments, L 3 does not exist.

[0171] In some embodiments, each L 1 are independently expressed as [ka] (In the formula, R 16is H, Each R 17 and R 17’ are independently H, C1-C6 alkyl, or —C(O)OH; R 18 are independently H, C6 to C 10 Aryl, -OH-SH, -NHC(=NH ’ )NH2 or -C(O)OH, C6 to C 10 each hydrogen atom in the aryl is independently optionally replaced by a halogen; Each L 2 are independently expressed as [ka] (In the formula, R 31 and R 31’ is H, R 36 is H); and Each L 3 are independently -C(O)C3-C6 cycloalkylene-(CH2) r NH-, -(CR 39 R 39’ ) r C(O)-, -C(O)(CR 39 R 39’ ) r -, -NH(CR 39 R 39’ ) r -, -(CR 39 R 39’ ) r NH-, -NH(CR 39 R 39’ ) r NH-, -NH(CH2CH2O) rp -(CR 36 R 36’ ) t C(O)-, -C(O)(CR 36 R 36’ ) t -(OCR 39 R 39’ CR 39 R 39’ ) rp-NH-, -C(O)(CR 36 R 36’ ) r -O-(C6~C 10 Aryl)-(CR 36’’ R 36’’’ ) t NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t C(O)-, -C(O)-(CR 36 R 36’ ) r -NH-C(O)-(C6~C 10 Aryl)-NH-, -NR 37 -(C6~C 10 aryl)-C(O)-NH-(CR 36 R 36’ ) r -C(O)-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -, -(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-, -NH(CR 36 R 36’ ) r -(C6~C 10 Aryl)-O-(CR 36’’ R 36’’’ ) t -NH- or -NH-(CR 36’’ R 36’’’ ) t -O-(C6~C 10 Aryl)-(CR 36 R 36’ ) r -NH-; During the ceremony, Each R 36 , R 36’ , R36’’ , R 36’’’ , R 39 and R 39’ are independently H or —COOH; each r is independently 1, 2, 3, 4, or 5; and Each t is independently 1, 2, 3, 4, or 5.

[0172] In some embodiments, when k is greater than 3, L in formula (I) x At least two of the following groups (referred to herein as "certain L") are independently x (also called "base"): [ka] is selected from.

[0173] In some embodiments, when k is greater than 3, L in formula (I) x At least three of the x is selected from the group

[0174] In some embodiments, when k is greater than 4, L in formula (I) x At least three of the x is selected from the group

[0175] In some embodiments, when k is greater than 4, L in formula (I) x At least three of the x is selected from the group

[0176] In some embodiments, when k is greater than 3, L in formula (I) x At least k-2 of the x is selected from the group

[0177] In some embodiments, when k is greater than 3, L in formula (I) x At least k-1 of the xis selected from the group

[0178] In some embodiments, when k is greater than 4, L in formula (I) x At least k-2 of the x is selected from the group

[0179] In some embodiments, when k is greater than 4, L in formula (I) x At least k-1 of the x is selected from the group

[0180] In some embodiments, when k is greater than 3, L in formula (I) x At least two of the L independently represent the following groups (referred to herein as "further specific L"): x (also called "base"): [ka] is selected from.

[0181] In some embodiments, when k is greater than 3, L in formula (I) x At least three of the groups independently represent a further specific L x is selected from the group

[0182] In some embodiments, when k is greater than 4, L in formula (I) x At least three of the groups independently represent a further specific L x is selected from the group

[0183] In some embodiments, when k is greater than 4, L in formula (I) x At least three of the groups independently represent a further specific L x is selected from the group

[0184] In some embodiments, when k is greater than 3, L in formula (I) x At least k-2 of the above independently represent a further specific L xis selected from the group

[0185] In some embodiments, when k is greater than 3, L in formula (I) x At least k-1 of the x is selected from the group

[0186] In some embodiments, when k is greater than 4, L in formula (I) x At least k-2 of the above independently represent a further specific L x is selected from the group

[0187] In some embodiments, when k is greater than 4, L in formula (I) x At least k-1 of the x is selected from the group

[0188] In some embodiments, at least one L x teeth, [ka] is.

[0189] In some embodiments, at least one L x teeth, [ka] is.

[0190] In some embodiments, at least one L x teeth, [ka] is.

[0191] In some embodiments, at least one L x teeth, [ka] is.

[0192] In some embodiments, at least one L x teeth, [ka] is.

[0193] In some embodiments, one, two, or three L x are independently expressed as [ka] It is of the type.

[0194] In some embodiments, -(L x ) k - is a group of formula (III) [ka] Includes:

[0195] In some embodiments, -(L x ) k - includes a group of formula (III), and R 16 , R 37 and R 38 is H.

[0196] In some embodiments, -(L x ) k - includes a group of formula (III), and R 39 is -COOH.

[0197] A group The compounds described herein include a group A, which is a group that may contain a radioactive element. x ) k connects BL to A. A is a metal, a radioactive element, Si- 18 F, B-18 F or Al- 18 A may be a chelating group Ch which may include F, or A may be a radiolabeled prosthetic group PG. Compounds as described herein having a chelating group without a coordinated radioelement may be referred to as "non-radioactive." Compounds as described herein having a chelating group with a coordinated (chelated, complexed, or bound within Ch) radioelement may be referred to as "radioactive." Such "radioactive" compounds are also referred to as radiolabeled compounds.

[0198] It will be understood that the structure of the chelating group is not particularly limited. 18 F, B- 18 F or Al- 18 Any chelating group known in the art that can coordinate to F is suitable. Preferably, the chelating group is a radioactive element or Si- so that there is no substantial reduction of the chelated radioactive particle in vivo, which would harm non-target cells. 18 F, B- 18 F or Al- 18 It binds stably to F.

[0199] In some embodiments, Ch is [ka] [ka] [ka] and Ch is selected from the group consisting of a radioactive element, Si- 18 F, B- 18 F or Al- 18 It may contain F; * represents a covalent bond to the remainder of the compound.

[0200] In some embodiments, Ch is [ka] and Ch is selected from the group consisting of a radioactive element, Si- 18 F, B- 18 F or Al- 18 It may contain F; * represents a covalent bond to the remainder of the compound.

[0201] In some embodiments, Ch is [ka] and Ch is a radioactive element, Si- 18 F, B- 18 F or Al- 18 It may contain F; * represents a covalent bond to the remainder of the compound.

[0202] Unless otherwise indicated herein, whenever a structural formula of a chelating group Ch is shown herein, Ch is intended to be a chelating group, even if such a radioactive element Si- 18 F, B- 18 F or Al- 18 Even if F is not shown in the structural formula, i.e., compounds of the present disclosure containing such Ch groups may be either non-radioactive or radioactive compounds, the radioactive element, Si- 18 F, B- 18 F or Al- 18 It may contain F. For example, it may contain [ka] Expressions such as [ka] and M is intended to include radioactive compounds such as a radioactive element, Si-, unless it is otherwise specified (e.g., by referring to the compound as "non-radioactive," "not radiolabeled," etc., or as otherwise implied by, for example, a description in which the synthesis of a non-radioactive compound is described). 18 F, B- 18 F or Al- 18 It can be F.

[0203] The compounds of the present disclosure may be selected from metals, radioactive elements, Si- 18 F, B- 18 F or Al- 18 The compound may contain a chelating group Ch (ie, A in the compound of formula (I) is Ch), which may contain F, or the compound may contain a radiolabeled prosthetic group PG.

[0204] A is stably bonded to the Si- 18 F, B- 18 F or Al- 18 Compounds of the present disclosure in which A is a chelating group Ch containing F or A is a radiolabeled prosthetic group are particularly suitable for diagnosis and imaging of FR-expressing cells in a subject, such as FR-expressing cancer cells and tumors.

[0205] Radiolabeled prosthetic groups PG and methods for covalently attaching such prosthetic groups to amino acids and peptides are known in the art. See, for example, Fani et al., Theranostics 2012;2(5):481-501; and Richter and Wuest, Molecules 2014,19:20536-20556. Such methods can be used to prepare compounds of formula (I) of the present disclosure, such as (L x ) k The PG may be used for conjugation to form a covalently linked PG.

[0206] PG is 18 F, 75 Br, 76 Br, 77 Br, 80 Br, 80m Br,82 Br, 123 I, 124 I, 125 I, 131 I and 211 It may be radiolabeled with a radioactive halogen selected from the group consisting of At.

[0207] Examples of radiolabeled prosthetic group PGs include: [ka] These include, but are not limited to:

[0208] In some embodiments, A is a metal, a radioactive element, Si- 18 F, B- 18 F or Al- 18 is a chelating group Ch which may contain F.

[0209] In some embodiments, A may include a metal or a radioactive element, but is not limited to Si- 18 F, B- 18 F or Al- 18 It is a chelating group Ch that is not an F group.

[0210] In some embodiments, A may include a radioactive element, but is not limited to Si- 18 F, B- 18 F or Al- 18 It is a chelating group Ch that is not an F group.

[0211] In some embodiments, A is a metal, a radioactive element, Si- 18 F, B- 18 F or Al- 18 A chelating group Ch containing F.

[0212] In some embodiments, A is a metal-containing chelating group, Ch.

[0213] In some embodiments, A is a chelating group Ch that includes a radioactive element.

[0214] In some embodiments, A is, 111 In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 169 Er, 72 As, 97 Ru, 203 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52m Mn, 177 Lu, 161 Tb, 169 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117m Sn, 213 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 123 I, 124 I, 125 I, 18 F, 149 Tb, 152 Tb, 155 Tb, 47 Sc, 44 Sc, 43 Sc, 225 Ac, 212 Pb, 211 At, 223 Ra, 227 Th, 131 I, 82 Rb, 76 As, 89 Zr, 111 Ag, 165 Er, 227 Ac, and 61and a chelating group Ch containing a radioactive element selected from the group consisting of Cu.

[0215] In some embodiments, A is 169 Er, 64 Cu, 67 Cu, 186 Re, 188 Re, 90 Y, 177 Lu, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 121 Sn, 213 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 149 Tb, 47 Sc, 225 Ac, 212 Pb, 211 At, 223 Ra, 227 Th, 131 I, 76 As, 111 Ag, 165 Er, and 227 and a chelating group Ch containing a radioactive element selected from the group consisting of Ac.

[0216] In some embodiments, A is 111 In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 72 As, 97 Ru, 203 Pb, 62 Cu, 64 Cu, 86 Y, 51 Cr, 52m Mn, 177 Lu, 169 Yb, 151 Pm, 172Tm, 117m Sn, 123 I, 124 I, 125 I, 18 F, 152 Tb, 155 Tb, 44 Sc, 43 Sc, 82 Rb, 89 Zr, and 61 and a chelating group Ch containing a radioactive element selected from the group consisting of Cu.

[0217] In some embodiments, A is 66 Ga, 67 Ga, 68 Ga, 177 Lu, and 225 and a chelating group Ch containing a radioactive element selected from the group consisting of Ac.

[0218] In some embodiments, A is 177 Lu or 225 A chelating group Ch containing a radioactive element Ac.

[0219] In some embodiments, A is 177 The chelating group Ch contains Lu.

[0220] In some embodiments, A is 225 A chelating group Ch containing Ac.

[0221] In some embodiments, A is Si- 18 F, B- 18 F or Al- 18 A chelating group Ch containing F.

[0222] In some embodiments, A is the prosthetic group PG.

[0223] Compound Synthesis and Intermediates The present disclosure further provides intermediate compounds (also referred to as intermediates) used to make the compounds described herein.

[0224] One embodiment is an intermediate compound described (explicitly or implicitly) in any one of Examples 1-52.

[0225] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0226] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0227] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0228] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0229] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0230] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0231] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0232] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0233] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0234] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0235] A further embodiment is a compound of the formula [ka] (In the formula, [ka] is an intermediate compound that represents a resin suitable for solid phase peptide synthesis (e.g., Wang resin) or H (e.g., when the intermediate is removed from the resin).

[0236] A further embodiment is a compound of the formula [ka] It is an intermediate compound of

[0237] The present disclosure further provides methods of synthesis for the disclosed compounds and intermediate compounds.

[0238] One embodiment is a method of synthesis as described (explicitly or implicitly) in any one of Examples 1-52.

[0239] One embodiment comprises: (a) Formula (I-1) [ka] providing an intermediate compound bound to a resin (e.g., Wang resin); (b) Compound (I-1) was reacted with Fmoc-Asp-O t By coupling with Bu, the compound represented by formula (I-2) [ka] forming an intermediate compound of (c) coupling compound (I-2) with Fmoc-2-Nal-OH to obtain a compound of formula (I-3) [ka] forming an intermediate compound of (d) coupling compound (I-3) with Fmoc-Gly-OH to obtain a compound of formula (I-4) [ka] forming an intermediate compound of (e) coupling compound (I-4) with DOTA-ONHS to obtain a compound of formula (I-5) [ka] forming an intermediate compound of (f) cleaving compound (I-5) from the resin; and (g) Pteryl N 10 -TFA deprotection to give the formula [ka] forming a compound of formula (I).

[0240] A further embodiment is (a) Formula (I'-1) [ka] providing an intermediate compound bound to a resin (e.g., Wang resin); (b) Compound (I'-1) [ka] and coupling with the compound of formula (I'-2) [ka] forming an intermediate compound of (c) coupling compound (I'-2) with Fmoc-Gly-OH to obtain a compound of formula (I'-3) [ka] forming an intermediate compound of (d) coupling compound (I'-3) with DOTA-ONHS to obtain a compound of formula (I'-4) [ka] forming an intermediate compound of (e) cleaving compound (I'-4) from the resin; and (f) Pteryl N 10 -TFA group to give a compound of formula [ka] forming a compound of formula (I).

[0241] A further embodiment is [ka] of [ka] React with [ka] In certain embodiments, the reaction is under strong basic conditions. In even more particular embodiments, the reaction is under strong basic conditions using K2CO3. In even more particular embodiments, the reaction is under strong basic conditions using K2CO3 at a temperature between about 15°C and about 35°C, and the reaction is carried out for about 2-6 hours. In even more particular embodiments, the reaction is under strong basic conditions using K2CO3 at a temperature between about 18°C ​​and about 28°C, and the reaction is carried out for about 2.5-3.5 hours. In even more particular embodiments, the reaction is under strong basic conditions using K2CO3 at a temperature between about 20°C and about 25°C, and the reaction is carried out for about 3 hours. In even more particular embodiments of the above embodiment or any particular embodiment thereof, between about 2 and about 4 equivalents of K2CO3 are used, preferably about 3 equivalents of K2CO3 (e.g., 3.0 mM Fmoc-Tyr-O t For Bu, this would mean about 9 mM KCO. In further particular embodiments of the above embodiment or any particular embodiment thereof, between about 2 and about 4 equivalents of KCO are used, preferably about 3 equivalents of KCO (e.g., 3.0 mM Fmoc-Tyr-O t For Bu, this would mean about 9 mM K2CO3) is used and the reaction is carried out in a mixture containing acetone (typically dry acetone).

[0242] As used herein, the term "alkyl" includes a chain of carbon atoms that is optionally branched and contains 1 to 20 carbon atoms. In certain embodiments, alkyl includes C1 to C 12 , C1~C 10Limited lengths, including C1-C9, C1-C8, C1-C7, C1-C6, and C1-C4, may be advantageous, and illustratively such particularly limited length alkyl groups, including C1-C8, C1-C7, C1-C6, and C1-C4, may be referred to as "lower alkyl." Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted. Exemplary substituents include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo, (═O), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or as described in various embodiments provided herein. It will be understood that "alkyl" may be combined with other groups, such as those provided above, to form functionalized alkyls. As an example, the combination of an "alkyl" group and a "carboxy" group, as described herein, can be referred to as a "carboxyalkyl" group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.

[0243] As used herein, the term "alkenyl" includes a chain of carbon atoms that is optionally branched, contains 2 to 20 carbon atoms, and also includes at least one carbon-carbon double bond (i.e., C=C). In certain embodiments, alkenyl includes C2 to C 12It will be understood that limited lengths, including C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4, may be advantageous. Illustratively, such particularly limited length alkenyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4, may be referred to as lower alkenyl. Alkenyls can be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Exemplary alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

[0244] As used herein, the term "alkynyl" includes a chain of carbon atoms that is optionally branched, contains 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e., C≡C). In certain embodiments, each alkynyl is selected from C2 to C 12 It will be understood that limited lengths, including C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4, may be advantageous. Illustratively, such particularly limited length alkynyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4, may be referred to as lower alkynyl. Alkenyls can be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Exemplary alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

[0245] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic group of 6 to 12 carbon atoms having a fully conjugated pi-electron system. In certain embodiments, aryl is a C6-C 10It will be understood that limited size groups such as aryl may be advantageous. Exemplary aryl groups include, but are not limited to, phenyl, naphthalenyl, and anthracenyl. Aryl groups may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein.

[0246] As used herein, the term "cycloalkyl" refers to a 3- to 15-membered all-carbon monocyclic ring, an all-carbon 5-membered / 6-membered or 6-membered / 6-membered fused bicyclic ring, or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group, where one or more of the rings may contain one or more double bonds, but the cycloalkyl does not contain a completely conjugated pi-electron system. In certain embodiments, cycloalkyl is a C3-C6 13 It will be understood that limited sizes such as C, C-C, C-C, and C-C may be advantageous. Cycloalkyl can be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like.

[0247] As used herein, the term "heterocycloalkyl" refers to a monocyclic or fused ring group having 3 to 12 ring atoms in the ring, where at least one ring atom is a heteroatom such as nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon atoms. Heterocycloalkyls can optionally contain 1, 2, 3, or 4 heteroatoms. Heterocycloalkyls can also have one additional double bond, including a double bond to nitrogen (e.g., C=N or N=N), but do not contain a fully conjugated pi-electron system. It will be understood that in certain embodiments, heterocycloalkyls of limited size, such as 3- to 7-membered heterocycloalkyls, 5- to 7-membered heterocycloalkyls, etc., may be advantageous. Heterocycloalkyls can be unsubstituted or substituted as described for alkyls or as described in the various embodiments provided herein. Exemplary heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, and the like.

[0248] As used herein, the term "heteroaryl" refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing 1, 2, 3, or 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon atoms, and also having a fully conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryls may be advantageously of limited size, such as 3- to 7-membered heteroaryls, 5- to 7-membered heteroaryls, etc. Heteroaryls can be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Exemplary heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazolyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, and carbazoloyl.

[0249] As used herein, "hydroxy" or "hydroxyl" refers to an --OH group.

[0250] As used herein, "alkoxy" refers to both an -O-(alkyl) or an -O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0251] As used herein, "aryloxy" refers to an -O-aryl or an -O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like.

[0252] As used herein, "mercapto" refers to the group --SH.

[0253] As used herein, "alkylthio" refers to the group -S-(alkyl) or -S-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

[0254] As used herein, "arylthio" refers to the group -S-aryl or -S-heteroaryl. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.

[0255] As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0256] As used herein, "trihalomethyl" refers to a methyl group having three halo substituents, such as a trifluoromethyl group.

[0257] As used herein, "cyano" refers to the group --CN.

[0258] As used herein, "sulfinyl" refers to the group -S(O)R'', where R'' is any R group as described in the various embodiments provided herein, or R'' can be a hydroxyl group.

[0259] As used herein, "sulfonyl" refers to the group -S(O)R'', where R'' is any R group as described in the various embodiments provided herein, or R'' can be a hydroxyl group.

[0260] As used herein, "S-sulfonamide" refers to a -S(O)NR"R" group, where R" is any R group as described in the various embodiments provided herein.

[0261] As used herein, "N-sulfonamido" refers to the -NR"S(O)2R" group, where R" is any R group as described in the various embodiments provided herein.

[0262] As used herein, "O-carbamyl" refers to an -OC(O)NR"R" group, where R" is any R group as described in the various embodiments provided herein.

[0263] As used herein, "N-carbamyl" refers to the group R"OC(O)NR"-, where R" is any R group as described in the various embodiments provided herein.

[0264] As used herein, "O-thiocarbamyl" refers to an -OC(S)NR"R" group, where R" is any R group as described in the various embodiments provided herein.

[0265] As used herein, "N-thiocarbamyl" refers to the group R"OC(S)NR"-, where R" is any R group as described in the various embodiments provided herein.

[0266] As used herein, "amino" refers to the group --NR"R" where R" is any R group as described in the various embodiments provided herein.

[0267] As used herein, "C-amido" refers to a -C(O)NR"R" group, where R" is any R group as described in the various embodiments provided herein.

[0268] As used herein, "N-amido" refers to an R"C(O)NR"- group, where R" is any R group as described in the various embodiments provided herein.

[0269] As used herein, "nitro" refers to the group --NO.sub.2.

[0270] As used herein, "bond" refers to a covalent bond.

[0271] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl may, but need not, be present, and that the description includes situations where the heterocyclic group is substituted with an alkyl group and situations where the heterocyclic group is not substituted with an alkyl group.

[0272] As used herein, "independently" means that the event or circumstance described thereafter is read by itself relative to other similar events or circumstances. For example, in a situation where several equivalent hydrogen groups are optionally replaced by another group described in the situation, the use of "independently optionally" means that each instance of a hydrogen atom on the group may be replaced by another group, and the groups replacing each of the hydrogen atoms may be the same or different. Or, for example, where there are multiple groups, all of which are selected from a set of possibilities, the use of "independently" means that each of the groups may be selected from a set of possibilities separate from any other group, and the groups selected in that situation may be the same or different.

[0273] Depending on the selection of starting materials and procedures, compounds may exist in one of the possible stereoisomers or as a mixture thereof, for example, as pure optical isomers or as stereoisomeric mixtures, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present disclosure is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When compounds contain double bonds, the substituents may be in the E- or Z-configuration. When compounds contain disubstituted cycloalkyls, the cycloalkyl substituents may have cis- or trans-configurations. All tautomeric forms (e.g., of pteryl groups) are also intended to be included.

[0274] With respect to compounds specifically listed as excluded from the present invention, all possible stereoisomers, mixtures of stereoisomers, tautomers, and salt forms of these compounds are also intended to be excluded.

[0275] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present disclosure. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are not typically biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. When both a basic group and an acidic group are present in the same molecule, the compounds of the present disclosure may also form internal salts, e.g., zwitterionic molecules.

[0276] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0277] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0278] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0279] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0280] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0281] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0282] In another aspect, the present disclosure provides a compound of formula (I) comprising acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate and the like. In some embodiments, the compounds of the present disclosure are provided in the form of a salt, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate salt.

[0283] Any formula given herein is intended to represent unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen.

[0284] As used herein, "amino acid" refers to any molecule, whether natural or synthetic (including non-protogeneic), that contains an alpha-carbon atom covalently bonded to an amino group and an acid group. The acid group may be a carboxyl group. Other suitable acid functional groups are those that can be included in polymers of naturally occurring amino acids. The term "amino acid" refers to a molecule of the formula: [ka] (wherein R' is a linear or branched C1-C1 alkyl group, in which one or more -H is optionally replaced by -NH2, -CO2H, -OH, -C(O)NH2, -SH, -SCH3, -NHC(=NH2)NH2). 12 and a side chain such as an alkyl group, an aryl group such as a phenyl group or a hydroxyphenyl group, a heteroaryl group such as an imidazolyl group or an indolyl group, a cycloalkyl group, or a heterocycloalkyl group such as a pyrrolidinyl group, wherein the ring Φ contains at least three carbon atoms.

[0285] Exemplary amino acids include naturally occurring amino acids, their analogs, derivatives, and congeners, amino acid analogs having atypical side chains, and all stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes both D- or L-optical isomers and peptidomimetics.

[0286] Exemplary amino acid groups include lysine (Lys), asparagine (Asn), threonine (Thr), serine (Ser), isoleucine (Ile), methionine (Met), proline (Pro), histidine (His), glutamine (Gln), arginine (Arg), glycine (Gly), aspartic acid (Asp), glutamic acid (Glu), alanine (Ala), valine (Val), phenylalanine (Phe), leucine (Leu), tyrosine (Tyr), cysteine ​​(Cys), tryptophan (Trp), phosphoserine (PSER), sulfo-cysteine, and acetylcysteine. These include, but are not limited to, the 20 endogenous human amino acids and their derivatives, such as glutaminosuccinic acid (ASA), hydroxyproline, citrulline (CIT), 1,3-methylhistidine (ME-HIS), alpha-amino-adipic acid (AAA), alpha-amino-butanoic acid (BABA), L-allo-cystathionine (cystathionine-A; CYSTA-A), L-cystathionine (cystathionine-B; CYSTA-B), cystine, allo-isoleucine (ALLO-ILE), ornithine (ORN), homocysteine ​​(HCY), and derivatives thereof. It will be understood that each of these examples is also contemplated in the D-configuration as described above in connection with the present disclosure. Specifically, for example, D-lysine (D-Lys), D-asparagine (D-Asn), D-threonine (D-Thr), D-serine (D-Ser), D-isoleucine (D-Ile), D-methionine (D-Met), D-proline (D-Pro), D-histidine (D-His), D-glutamine (D-Gln), D-arginine (D-Arg), D-glycine ( These include D-Gly, D-aspartic acid (D-Asp), D-glutamic acid (D-Glu), D-alanine (D-Ala), D-valine (D-Val), D-phenylalanine (D-Phe), D-leucine (D-Leu), D-tyrosine (D-Tyr), D-cysteine ​​(D-Cys), D-tryptophan (D-Trp), and D-citrulline (D-CIT).

[0287] As used herein, the term "amino acid residue" refers to the portion of an amino acid remaining after the amino acid is covalently bonded to two portions of a compound containing the amino acid residue: (1) via the alpha-acid group (typically alpha-carboxyl) and alpha-amino group of the amino acid (e.g., α-Asp) or (2) via the side chain (R') acid group (typically carboxyl) or the side chain (R') amino group and the alpha-acid group (typically alpha-carboxyl) and alpha-amino group of the amino acid (e.g., β-Asp).

[0288] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0289] It will be understood that amino acids, when used in connection with the compounds and conjugates described herein, may exist as zwitterions in the conjugates into which they are incorporated.

[0290] As used herein, "sugar" refers to a carbohydrate, such as a monosaccharide, disaccharide, or oligosaccharide. In the context of the present disclosure, monosaccharides are preferred. Non-limiting examples of sugars include erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altose, glucose, mannose, galactose, ribulose, fructose, sorbose, tagatose, and the like. In the context of the present disclosure, sugars will be understood to include cyclic isomers of amino sugars, deoxy sugars, acid sugars, and combinations thereof. Non-limiting examples of such sugars include galactosamine, glucosamine, deoxyribose, fucose, rhamnose, glucuronic acid, ascorbic acid, and the like. In some embodiments, sugars for use in the context of the present disclosure include: [ka] Examples include:

[0291] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, combined with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0292] The pharmaceutical compositions of the invention may include a "therapeutically effective amount" or a "prophylactically effective amount" of a compound of the invention.

[0293] A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount according to the present invention will depend on the individual's disease state, age, sex, and weight, as well as the radiolabeled (e.g., 177 The therapeutically effective amount may also vary depending on factors such as the ability of the FR therapeutic agent, such as a compound of formula (I) (e.g., a radiolabeled compound, optionally in combination with an additional therapeutic agent, to induce FR). 177 Any toxic or detrimental effects of the FR therapeutic agent, such as a compound of formula (I), are outweighed by the therapeutically beneficial effects.

[0294] A "therapeutically effective dose" can inhibit a measurable parameter, e.g., tumor growth rate, by at least about 20%, at least about 40%, at least about 60%, or at least about 80% compared to untreated controls. The ability of the combinations according to the invention to inhibit a measurable parameter, e.g., cancer, can be assessed in animal model systems that are predictive of efficacy in human tumors. Alternatively, this property of a composition can be evaluated by testing the ability of the combinations according to the invention to inhibit, and such inhibition can be assessed in vitro by assays known to those skilled in the art.

[0295] A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount may be less than the therapeutically effective amount.

[0296] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0297] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer to reducing or ameliorating the progression, severity, and / or duration of the disorder, e.g., a proliferative disorder such as cancer, or improving one or more symptoms (e.g., one or more discernible symptoms) of the disorder resulting from the administration of one or more therapies or therapeutic agents; or reducing or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible to the patient. In certain embodiments, the terms "treat," "treatment," and "treating" refer to improving at least one measurable physical parameter of a proliferative disorder such as cancer, e.g., tumor growth that is not necessarily discernible by the patient. In other embodiments, the terms "treat," "treatment," or "treating" refer to inhibiting the progression of a proliferative disorder such as cancer, either physically, e.g., by stabilizing a discernible symptom, physiologically, e.g., by stabilizing a physical parameter, or both. In other embodiments, the terms "treat," "treatment," or "treating" refer to reducing or stabilizing tumor size or the number of cancerous cells.

[0298] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or the delay in the onset or progression of the disease or disorder.

[0299] The term "anti-cancer effect" refers to a biological effect that can be manifested by various means, including, but not limited to, a reduction in tumor volume, a reduction in the number of cancer cells, a reduction in the number of tumor metastases, an increase in life expectancy, a reduction in cancer cell proliferation, a reduction in cancer cell survival, or an improvement in various physiological symptoms associated with a cancerous condition. An "anti-cancer effect" can also be manifested by the ability of the therapeutic agents described herein (e.g., peptides, polynucleotides, cells, small molecules, and antibodies) to prevent the development of cancer at the initial site.

[0300] The term "anti-tumor effect" refers to a biological effect that may be manifested by various means, including, but not limited to, a reduction in tumor volume, a reduction in tumor cell number, a reduction in tumor cell proliferation, or a reduction in tumor cell survival.

[0301] The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of abnormal cells, but may include benign cancers. In various embodiments, cancer cells can spread locally or to other parts of the body through the bloodstream and lymphatic system. In some aspects, the cancer is an FR-expressing cancer. In some embodiments, the cancer is an FR-α-expressing cancer. Examples of various cancers are described herein. For example, cancers may include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, thyroid cancer, renal clear cell carcinoma, transitional cell carcinoma of the bladder, colon adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic ductal carcinoma, non-small cell lung cancer, soft tissue sarcoma, and the like. Other exemplary cancers include, but are not limited to, small cell lung cancer, bone cancer, head and neck cancer, hepatocellular carcinoma, cutaneous or intraocular melanoma, uterine cancer, stomach cancer, colon cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, gastric and esophagogastric cancer, cancers of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the urethra, cancer of the penis, cancer of the ureter, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, inflammatory myofibroblastoma, and combinations thereof.

[0302] The terms "tumor" and "cancer" are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., disseminated or circulating tumors. As used herein, the term "cancer" or "tumor" includes precancerous as well as malignant cancers and tumors and benign cancers. As used herein, the term "cancer" includes primary malignant cells or tumors (e.g., those in which cells have not metastasized to sites within a subject's body other than the site of the original malignant tumor or tumor) and secondary malignant cells or tumors (e.g., those resulting from metastasis, which is the metastasis of malignant cells or tumor cells to a secondary site different from the site of the original tumor).

[0303] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0304] As used herein, the terms "a," "an," and "the," as well as similar terms used in connection with this disclosure (particularly in connection with the claims), are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0305] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. Any examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to further clarify the invention and do not limit the scope of the invention as otherwise claimed.

[0306] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present disclosure can be present in racemic form or enriched in one enantiomer, for example, in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms having unsaturated double bonds may, where possible, be present in cis-(Z)- or trans-(E)-form.

[0307] Thus, as used herein, the compounds of the present disclosure may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as a substantially pure geometric (cis or trans) stereoisomer, diastereomer, optical isomer (enantiomer), racemate, or mixtures thereof.

[0308] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization on the basis of the physical chemical differences of the constituent components.

[0309] Any resulting racemic forms of the compounds or intermediates of the present disclosure can be resolved into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. In particular, compounds of the present disclosure can be resolved into their optical antipodes by fractional recrystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using such basic moieties. Racemic compounds or racemic intermediates of the present disclosure can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC), using a chiral adsorbent.

[0310] radioactive elements The chelating group of the FR targeting compounds described herein can include a radioactive element.

[0311] In some embodiments, the radioactive element is 225 Ac or 177 This is Lu.

[0312] 177 Lu has a half-life of 6.7 days. It travels chaotically within tissues over approximately 20-80 cells or 0.5-2 mm, emitting 0.5 MeV of energy consisting of negatively charged beta particles (electrons) that cause primarily base damage and single-strand breaks (i.e., fractures). At high doses, these breaks can interact to convert sublethal damage (SLD) or potentially lethal damage (PLD) into irreversible lethal damage. 177 Lu also emits 113 Kv and 208 kV radiation that can be used for diagnostic imaging.

[0313] 225 Ac, in contrast, has a half-life of 9.9 days and emits alpha particles with an energy of 8.38 MV. Only 0.5% of the energy is emitted as photon radiation at 142 Kv. Thus, the majority of radiation particles are positively charged and are approximately 8,000 times more powerful than beta particles. Furthermore, the energy from these particles is deposited over a relatively short distance (2-3 cells). As a result, there is dense and severe tissue damage in the form of double-strand breaks with multiplied damage sites resulting in irreparable, lethal damage. This is called high linear energy transfer (LET) or high-density ionization, and results in an absorbed dose 3-7 times greater than that of beta particles. Either isotope ( 177 Lu or 225 The type of cell damage caused by each warhead is expected to differ due to differences in the characteristics of each warhead. 177 Lu is thought to result in a longer radiation path length and therefore may be more effective at delivering radiation to neighboring cells. The predominance of single-strand breaks, especially in the presence of oxygen, provides an opportunity to repair sublethal damage (SLD) and / or potentially lethal damage (PLD), providing optimal conditions for normal tissue repair. Conversely, 225 Ac emits very potent, high-LET radiation, and the potential for normal tissue repair is much more limited. The radiobiological effectiveness of alpha radiation is at least five times that of beta radiation, and the relative biological effectiveness (RBE) must be considered in relation to the administered dose. 225 The type of DNA damage delivered by Ac therapy does not require the presence of oxygen and may therefore be more effective in hypoxic tumor regions.

[0314] Suitable radioactive elements include: 111 In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 169 Er, 72 As, 97 Ru,203 Pb, 62 Cu, 64 Cu, 67 Cu, 186 Re, 188 Re, 86 Y, 90 Y, 51 Cr, 52m Mn, 177 Lu, 161 Tb, 169 Yb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 172 Tm, 121 Sn, 117m Sn, 213 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 123 I, 124 I, 125 I, 18 F, 149 Tb, 152 Tb, 155 Tb, 47 Sc, 44 Sc, 43 Sc, 225 Ac, 212 Pb, 211 At, 223 Ra, 227 Th, 131 I, 82 Rb, 76 As, 89 Zr, 111 Ag, 165 Er, 227 Ac, and 61 Cu is an example.

[0315] Suitable radioactive elements for therapeutic use of the FR-targeted compounds disclosed herein include: 169 Er, 64 Cu, 67 Cu, 186 Re, 188 Re, 90 Y, 177Lu, 161 Tb, 175 Yb, 105 Rh, 166 Dy, 166 Ho, 153 Sm, 149 Pm, 151 Pm, 121 Sn, 213 Bi, 142 Pr, 143 Pr, 198 Au, 199 Au, 149 Tb, 47 Sc, 225 Ac, 212 Pb, 211 At, 223 Ra, 227 Th, 131 I, 76 As, 111 Ag, 165 Er, and 227 Examples include, but are not limited to, Ac.

[0316] Suitable radioactive elements for diagnostic use of the FR-targeted compounds disclosed herein include: 111 In, 99m Tc, 94m Tc, 67 Ga, 66 Ga, 68 Ga, 52 Fe, 72 As, 97 Ru, 203 Pb, 62 Cu, 64 Cu, 86 Y, 51 Cr, 52m Mn, 177 Lu, 169 Yb, 151 Pm, 172 Tm, 117m Sn, 123 I, 124 I, 125 I, 18 F, 152 Tb, 155 Tb, 44 Sc, 43 Sc, 82 Rb, 89 Zr, and61 These include, but are not limited to, Cu.

[0317] metal The chelating groups of the FR-targeted compounds described herein can include metals suitable for diagnostic imaging.

[0318] Suitable metals for diagnostic uses such as nuclear magnetic resonance of the FR targeting compounds disclosed herein include metal ions that exhibit paramagnetic properties (e.g., paramagnetic ions of metals selected from the group consisting of Co, Mn, Cu, Cr, Ni, V, Au, Fe, Eu, Gd, Dy, Tb, Ho, and Er).

[0319] Suitable metals for diagnostic and other uses of x-rays in the FR targeting compounds disclosed herein include metal ions that absorb x-rays (e.g., ions of metals selected from the group consisting of Re, Sm, Ho, Lu, Pm, Y, Bi, Pb, Os, Pd, Gd, La, Au, Yb, Dy, Cu, Rh, Ag, and Ir).

[0320] Albumin-binding moiety For example, the FR-targeting compounds of the present disclosure in any one of embodiments 1 to 56 can be optionally substituted with albumin-binding moieties, such as Evans Blue and its derivatives, and 4-(p-iodophenyl)butanoic acid. This substitution can be achieved by substituting the group L x or A (chelating group Ch or prosthetic group PG). Albumin binding moieties and related linking chemistries are known in the art. See, for example, the review article by Lau et al., Bioconjugate Chem. 2019, 30, 487-502, and the references cited therein.

[0321] combination The combinations of the present disclosure include the FR-targeting compounds of the present disclosure (e.g., compounds of formula (I) that may include a radioactive element complexed by the chelating group of the compound) and one or more additional therapeutic agents as described below, which can be administered to patients to treat proliferative diseases such as cancer, particularly FR-expressing cancer. The additional therapeutic agent can be any of the therapeutic agents described herein.

[0322] In one embodiment of the combination for the uses or methods described herein, the FR-targeted compound is radiolabeled (i.e., contains a complexed radioelement), and the compound comprises: 177 Lu and 225 In one particular embodiment, the radioactive element is selected from: Ac 177 In another embodiment, a compound radiolabeled with Lu is administered. 225 In yet another embodiment, a compound radiolabeled with Ac is administered. 177 Lu-radiolabeled compounds, and 225 Both the compound radiolabeled with Ac are administered. The FR targeting compound can be administered in a parenteral dosage form. In some embodiments, the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.

[0323] In various embodiments, the FR targeting compound (e.g., of formula (I)) is 177 The amount radiolabeled with Lu and administered is about 0.1 GBq to about 15 GBq. 177 The total dose of FR-targeted compound radiolabeled with Lu ranges from about 1 GBq to about 200 GBq.

[0324] In various embodiments, the FR targeting compound (e.g., of formula (I)) is 225 The dose radiolabeled with Ac and administered is about 1 MBq to about 20 MBq.

[0325] In other aspects, the combinations and methods described herein further comprise imaging FR expression by cancer. In some embodiments, the imaging step is performed before the step of administering a FR targeting compound, such as a radiolabeled compound of Formula (I). In other embodiments, the imaging step is performed after the step of administering a FR targeting compound, such as a radiolabeled compound of Formula (I).

[0326] In various embodiments, the imaging method is selected from the group consisting of single photon emission computed tomography (SPECT) imaging, positron emission tomography imaging, immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH). In some embodiments, the imaging is performed by SPECT imaging.

[0327] In some embodiments, the combinations described herein include a FR-targeting compound described herein that is not radiolabeled.

[0328] In some embodiments, the combinations described herein include a radioactive element, or Si- 18 F, B- 18 F or Al- 18 The present invention also includes FR-targeting compounds described herein that contain F.

[0329] Additional therapeutic agents Combinations according to the present invention include a FR-targeting compound as described above, such as radiolabeled Compound I, and one or more additional therapeutic agents, such as cancer immunotherapy (IO) agents, as described below.

[0330] Cancer immunotherapy In various preferred embodiments, an IO agent can be used as an additional therapeutic agent in conjunction with an FR-targeting compound, such as the radiolabeled compounds of Formula (I) described herein. Any of the IO agents described in this section entitled "Cancer Immunotherapeutics" can be used in conjunction with an FR-targeting compound, such as the radiolabeled compounds of Formula (I) described herein, to treat cancer.

[0331] For example, PD-1 inhibitors can be used. The programmed death 1 (PD-1) protein is an inhibitory member of the extended CD28 / CTLA-4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14:391779-82; Bennett et al. (2003) J. Immunol. 170:711-8). Two ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), have been identified and shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carter et al. (2002) Eur. J. Immunol. 32:634-43). PD-L1 is enriched in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9).

[0332] PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signaling (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745). The interaction between PD-1 and PD-L1 can act as an immune checkpoint that can result in, for example, a reduction in tumor-infiltrating lymphocytes, a reduction in T cell receptor-mediated proliferation, and / or immune evasion by cancer cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction between PD-1 and PD-L2 is also blocked (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).

[0333] In certain embodiments, the combinations or methods as described herein include a PD-1 inhibitor as the IO agent. In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), pembrolizumab (Merck & Co), pidilizumab (CureTech), durvalomab, atezolizumab, avelumab, nivolumab (Bristol-Myers Squibb Company), MK-3475, MPDL3280A, MEDI4736, ipilimumab (Bristol-Myers Squibb Company), tremelimumab, MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune). In some embodiments, the PD-1 inhibitor is PDR001. PDR001 is also known as spartalizumab. In other embodiments, the PD-1 inhibitor is not pembrolizumab.

[0334] In certain embodiments, the combination or combination therapy includes, in addition to a FR-targeting compound of the present disclosure, one or more other therapeutic agents selected from an mTOR inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a GITR agonist (e.g., an anti-GITR antibody molecule), a TGF-β inhibitor, and an IL-15 / IL-15Ra complex.

[0335] In certain cases, the combination or combination therapy includes, in addition to the FR-targeted compound of the present disclosure, one or more other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea (or anti-emetic) agents, chemotherapeutic agents, pain-relieving agents, cytoprotective agents, and combinations thereof.

[0336] In other embodiments, the combination or combination therapy includes, in addition to the FR-targeting compounds of the present disclosure, a tyrosine kinase inhibitor; a vascular endothelial growth factor (VEGF) receptor inhibitor; a platelet-derived growth factor (PDGF) receptor inhibitor; a fibroblast growth factor receptor (FGFR) inhibitor; an Aurora kinase inhibitor; a cyclin-dependent kinase (CDK) inhibitor; a checkpoint kinase (CHK) inhibitor; a 3-phosphoinositide-dependent kinase-1 (PDK1 or PDPK1) inhibitor; a pyruvate dehydrogenase kinase (PDK) inhibitor; a protein kinase B (PKB) or AKT inhibitor; a protein kinase C (PKC) activator; a B-RAF inhibitor; a C-RAF inhibitor; a K RAS inhibitors; human granulocyte colony-stimulating factor (G-CSF) modulators; RET inhibitors; FMS-like tyrosine kinase 3 (FLT3) inhibitors or CD135; c-KIT inhibitors; Bcr / Abl kinase inhibitors; IGF-1R inhibitors; IGF-1R antibodies; PIM kinase inhibitors; MET inhibitors; human epidermal growth factor receptor 2 (HER2 receptor) (also known as Neu, ErbB-2, CD340, or p185 inhibitors); epidermal growth factor receptor (EGFR) inhibitors; EGFR antibodies; hedgehog antagonists; mTOR inhibitors; phosphoinositide 3-kinase (PI3K) inhibitors; BCL-2 inhibitors; mitogen-activated protein kinase (MEK) inhibitors; P38 MAPK inhibitors; JAK inhibitors; alkylating agents; aromatase inhibitors; topoisomerase I inhibitors; topoisomerase II inhibitors; DNA synthesis inhibitors; folate antagonists or antifolates; immunomodulators; pro-apoptotic receptor agonists (PARA) including DR4 (TRAILR1) and DR5 (TRAILR2); phospholipase A2 (PLA2) inhibitors; SRC inhibitors; osteoclastic bone resorption inhibitors; G protein-coupled somatostatin receptor inhibitors; interleukin-11 and synthetic interleukin-11 (IL-11); cell growth stimulators; receptor activator for nuclear factor kappa B (RANK) inhibitors; thrombopoietin-mimetic peptibodies; histone deacetylase (HDAC) inhibitors; antitumor antibiotics; antimicrotubule or mitotic inhibitors; plant alkaloids; taxane antineoplastic agents; cathepsin K inhibitors; epothilone B analogs; heat shock protein (HSP) inhibitors;Farnesyltransferase inhibitors (FTIs); thrombopoietin (TpoR) agonists; proteosome inhibitors; kinesis spindle protein (KSP) inhibitors (also known as Eg5 inhibitors); polo-like kinase (Plk) inhibitors; adrenal steroid inhibitors; antiandrogens; anabolic steroids; gonadotropin-releasing hormone (GnRH) receptor agonists; HPV vaccines; iron chelators; bisphosphonates; demethylating agents; retinoids; cytokines; estrogen receptor downregulators; antiestrogens; selective estrogen receptor modulators (SERMs); selective estrogen receptor degraders (SERDs); luteinizing hormone-releasing hormone (LHRH) agonists; progesterone; 17 α-hydroxylase / C17,20 lyase (CYP17A1) inhibitors; CC chemokine receptor 4 (CCR4) antibodies; CD20 antibodies; CD20 antibody-drug conjugates; CD22 antibody-drug conjugates; CD30 and one or more other therapeutic agents selected from the group consisting of mAb-cytotoxin conjugates; CD33 antibody-drug conjugates; CD40 antibodies; CD52 antibodies; anti-CS1 antibodies; CTLA-4 antibodies; TPH inhibitors; PARP (poly ADP-ribose polymerase) inhibitors; and radiosensitizers.

[0337] Examples of PARP (poly ADP ribose polymerase) inhibitors include, but are not limited to, olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zeluja), talazoparib, and veliparib.

[0338] Examples of radiosensitizers include, but are not limited to, idronoxyl (also known as Veyonda, NOX-66), sodium glycididazole, nimorazole, NBTXR3 (also known as PEP503), [Zr]AGuIX, lucantone, telomelysin (OBP-301), lonidamine, nimorazole, panobinostat, celecoxib, cilengitide, entinostat, etanidazole, and ganetespib (STA-9090).

[0339] Examples of folate antagonists or antifolates include, but are not limited to, trimetrexate glucuronate (Neutrexin®); piritrexim isethionate (BW201U); pemetrexed (LY231514); raltitrexed (Tomudex®); and methotrexate (Rheumatrex®, Trexal®).

[0340] In other embodiments, the combination or combination therapy includes, in addition to the FR targeting compound of the present disclosure, a DNA repair inhibitor. DNA repair inhibitors include single-strand repair inhibitors (e.g., PARP inhibitors) and inhibitors of double-strand (e.g., DNA-PK) repair mechanisms.

[0341] Some patients may experience allergic reactions to the compounds of the present disclosure and / or other anti-cancer agents during or after administration; therefore, anti-allergy agents are often administered to minimize the risk of an allergic reaction. Suitable anti-allergy agents include corticosteroids, such as dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, and hydrocortisone sodium phosphate, sold under the trade names Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), prednisolone (sold under the trade names Delta-Cortel®, Orapred®, Pediapred®, and Prelone®), prednisone (sold under the trade names Deltasone®, Liquid Red®, Meticorten®, and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, and sold under the trade names Duralone®, Medralone®, Medrol®, M-Prednisol®, and Solu-Medrol®); antihistamines such as diphenylhydramine (e.g., Benadryl®), hydroxyzine, and cyproheptadine; and bronchodilators such as the beta-adrenergic receptor agonist, albuterol (e.g., Proventil®), and terbutaline (Brethine®).

[0342] Some patients may experience nausea during and after administration of the compounds of the present disclosure and / or other anticancer agents; therefore, antiemetics are used to prevent nausea (upper abdominal) and vomiting. Suitable antiemetics include aprepitant (Emend®), ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®), dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof.

[0343] To make patients more comfortable, medications are often prescribed to alleviate the pain experienced during treatment. Common over-the-counter pain relievers, such as Tylenol®, are often used. However, for moderate or severe pain, opioid pain relievers, such as hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), and fentanyl (e.g., Duragesic®), are also useful.

[0344] Cytoprotective agents (e.g., neuroprotective agents, free radical scavengers, cardioprotective agents, anthracycline extravasation reversal agents, nutritional supplements, etc.) may be used as adjunctive therapy to protect normal cells from treatment toxicity and limit organ toxicity. Suitable cytoprotective agents include amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, cytovorm factor, and folinic acid).

[0345] The structures of the active compounds identified by code numbers, generic names or trade names can be obtained from the current edition of the standard compendium "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0346] The above-described compounds that can be used in combination with the FR targeting compounds of the present disclosure can be prepared and administered as described in the art, for example, in the documents cited above.

[0347] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a combination according to the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with other anti-cancer agents as previously described, in association with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject.

[0348] In one embodiment, the present disclosure provides a method of treating a human or animal subject suffering from a cell proliferative disorder, such as cancer, preferably a FR-expressing cancer.

[0349] The present disclosure provides a method of treating a human or animal subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a combination according to the invention or a pharmaceutically acceptable salt thereof, alone or in combination with other anti-cancer agents.

[0350] In particular, the combinations will be formulated together as a combined therapeutic agent or will be administered separately.

[0351] In combination therapy, the compounds of the present disclosure and other anti-cancer agents may be administered simultaneously, concurrently, or sequentially, without particular time limitations, and such administration provides therapeutically effective levels of the two compounds in the patient's body.

[0352] In a preferred embodiment, the combination and other anticancer agents of the present disclosure are generally administered sequentially in any order by injection or orally. The administration regimen may vary depending on the patient's stage of disease, physical condition, safety profile and tolerability of each individual agent, as well as other criteria familiar to the attending physician and doctor administering the combination. The combination and other anticancer agents of the present disclosure may be administered minutes, hours, days, or weeks apart, depending on the particular cycle being used in the treatment. Furthermore, the cycle may also include administering one agent more frequently than the other agent during the treatment cycle and at a different dose for each administration of the agent.

[0353] Combinations including FR therapeutic agents, such as the radiolabeled Compound I described herein, can also be usefully used in combination with known therapeutic processes, such as the administration of hormones or, particularly, radiation. The compounds of the present disclosure can be used, in particular, as radiosensitizers, especially for the treatment of tumors that are less sensitive to radiation therapy.

[0354] Use of FR-targeting compounds In one aspect, the FR-targeting compounds of the present disclosure, for example, of Formula (I), or pharmaceutically acceptable salts thereof, can be used, for example, for the treatment, diagnosis, and imaging of proliferative diseases associated with FR-expressing cells. Typically, the proliferative disease is cancer. Examples of compounds of Formula (I) include, but are not limited to, the compounds of embodiments 1-56, and embodiments thereof, including other specific and more specific embodiments thereof.

[0355] One embodiment is a method for treating FR-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the FR-targeting compound of the present disclosure, for example, a compound of formula (I) or its pharmaceutically acceptable salt, or a therapeutically effective amount of the pharmaceutical composition of the present disclosure.Usually, at least a portion of the effective amount of the compound administered to the subject comprises a radioactive element bound to the chelating group of the compound.In some particular embodiments, such a radioactive element is 177 Lu or 225 It is Ac.

[0356] A further embodiment is a method of treating a FR-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a FR-targeting compound of the present disclosure, e.g., a compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition thereof, wherein the compound: 177 This method has a chelating group Ch containing Lu.

[0357] A further embodiment is a method of treating a FR-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a FR-targeting compound of the present disclosure, e.g., a compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition thereof, wherein the compound: 225 This method has a chelating group Ch containing Ac.

[0358] A further embodiment is a method of treating a FR-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; 177 This method has a chelating group containing Lu.

[0359] A further embodiment is a method of treating a FR-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; 225 This method has a chelating group containing Ac.

[0360] A further embodiment is a method of treating a FR-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; 177 This method has a chelating group containing Lu.

[0361] A further embodiment is a method of treating a FR-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; 225 This method has a chelating group containing Ac.

[0362] In some embodiments, the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphatic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, and pituitary adenoma.

[0363] In some embodiments, the FR-expressing cancer is selected from the group consisting of ovarian cancer, endometrial cancer, brain cancer, lung cancer, kidney cancer, head and neck cancer, breast cancer, gastric cancer, and colorectal cancer.

[0364] In some embodiments, the FR-expressing cancer is selected from the group consisting of ovarian cancer, endometrial cancer, brain cancer, lung cancer, and kidney cancer.

[0365] In some embodiments, the FR-expressing cancer is selected from the group consisting of ovarian cancer and non-small cell lung cancer.

[0366] In some embodiments, the FR-expressing cancer is ovarian cancer.

[0367] In some embodiments, the FR-expressing cancer is non-small cell lung cancer.

[0368] Another embodiment is a method for treating FR-expressing tumors or cells, comprising contacting one or more FR-expressing tumors or cells with an effective amount of the FR-targeting compound of the present disclosure, for example, a compound of formula (I) or its pharmaceutically acceptable salt, or a therapeutically effective amount of the pharmaceutical composition of the present disclosure.Usually, at least a portion of the effective amount of the compound contacted with FR-expressing tumors or cells comprises a radioactive element bound to the chelating group of the compound.In some particular embodiments, such a radioactive element is 177 Lu or 225 It is Ac.

[0369] A further embodiment is a method of treating FR-expressing tumors or cells, comprising contacting one or more FR-expressing tumors or cells with an effective amount of the FR-targeting compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition thereof, wherein the compound: 177 This method has a chelating group Ch containing Lu.

[0370] A further embodiment is a method of treating FR-expressing tumors or cells, comprising contacting one or more FR-expressing tumors or cells with an effective amount of the FR-targeting compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition thereof, wherein the compound: 225 This method has a chelating group Ch containing Ac.

[0371] A further embodiment is a method of treating FR-expressing tumors or cells, comprising administering to the tumor or cells one or more FR-expressing tumors or cells an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; wherein the FR targeting compound is 177 This method has a chelating group containing Lu.

[0372] A further embodiment is a method of treating FR-expressing tumors or cells, comprising administering to the tumor or cells one or more FR-expressing tumors or cells an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; wherein the FR targeting compound is 225 This method has a chelating group containing Ac.

[0373] A further embodiment is a method of treating FR-expressing tumors or cells, comprising administering to the tumor or cells one or more FR-expressing tumors or cells an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; wherein the FR targeting compound is 177 This method has a chelating group containing Lu.

[0374] A further embodiment is a method of treating FR-expressing tumors or cells, comprising administering to the tumor or cells one or more FR-expressing tumors or cells an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; wherein the FR targeting compound is 225 This method has a chelating group containing Ac.

[0375] In some embodiments, the tumor or cell is associated with a cancer selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphatic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, and pituitary adenoma.

[0376] In some embodiments, the FR-expressing tumor or cell is associated with a cancer selected from the group consisting of ovarian cancer, endometrial cancer, brain cancer, lung cancer, kidney cancer, head and neck cancer, breast cancer, gastric cancer, and colorectal cancer.

[0377] In some embodiments, the FR-expressing tumor or cell is associated with a cancer selected from the group consisting of ovarian cancer, endometrial cancer, brain cancer, lung cancer, and kidney cancer.

[0378] In some embodiments, the cancer is selected from the group consisting of ovarian cancer and non-small cell lung cancer.

[0379] In some embodiments, the cancer is ovarian cancer.

[0380] In some embodiments, the cancer is non-small cell lung cancer.

[0381] A further embodiment is a method for imaging diagnosis of FR-expressing cancer in a subject, comprising administering to the subject an effective amount of an FR-targeting compound of the present disclosure, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of the present disclosure, wherein the compound comprises a metal, a radioactive element, or a radioactive halogen.

[0382] A further embodiment is a method for imaging a FR-expressing cancer in a subject, comprising administering to the subject an effective amount of the FR-targeting compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition thereof, wherein the compound: 177 This method has a chelating group Ch containing Lu.

[0383] A further embodiment is a method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of the FR-targeting compound of any one of embodiments 1-55, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition thereof, wherein the compound: 225 This method has a chelating group Ch containing Ac.

[0384] A further embodiment is a method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; 177 This method has a chelating group containing Lu.

[0385] A further embodiment is a method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; 68 This method has a chelate group containing Ga.

[0386] A further embodiment is a method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; 177 This method has a chelating group containing Lu.

[0387] A further embodiment is a method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; 68 This method has a chelate group containing Ga.

[0388] A further embodiment is a method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of an FR-targeting compound of any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition thereof, wherein the compound has a chelating group Ch containing a radioactive element or metal suitable for imaging.

[0389] A further embodiment is a method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; wherein the FR targeting compound has a chelating group containing a radioactive element or metal suitable for diagnostic imaging.

[0390] A further embodiment is a method for imaging FR-expressing cells in a subject, comprising administering to the subject an effective amount of a FR-targeting compound of the following structural formula: [ka] or a pharmaceutically acceptable salt thereof; wherein the FR targeting compound has a chelating group containing a radioactive element or metal suitable for diagnostic imaging.

[0391] In a further aspect, the present disclosure relates to the treatment of a subject in vivo using a combination comprising a FR-targeting compound of the present disclosure, such as a radiolabeled compound of Formula (I) (e.g., of any one of embodiments 1-56), and an additional therapeutic agent disclosed herein, or a composition or formulation comprising a combination disclosed herein, such that the growth of cancerous tumors is inhibited or reduced.

[0392] In some embodiments, the FR targeting compounds of the present disclosure, such as radiolabeled compounds of formula (I), or pharmaceutically acceptable salts thereof, can be used in combination with one or more standard therapies for treating the disorders herein (e.g., for cancer or infectious diseases), vaccines (e.g., therapeutic cancer vaccines), cell therapy, radiation therapy, surgery, or any other therapeutic agent or modality. For example, to achieve antigen-specific enhancement of immunity, the combination can be administered with an antigen of interest. In one embodiment, the combinations disclosed herein can be administered in any order or simultaneously.

[0393] In one embodiment, the therapies described herein may include compositions of the present disclosure co-formulated with and / or co-administered with one or more additional therapeutic agents as previously described, e.g., one or more anti-cancer agents, cytotoxic or cytostatic agents, hormonal therapy, vaccines, and / or other immunotherapy as previously described.

[0394] In further embodiments, the FR targeting compounds of the present disclosure, such as radiolabeled compounds of formula (I), or pharmaceutically acceptable salts thereof, are further administered or used in combination with other therapeutic treatment modalities, including surgery, radiation, cryosurgery, and / or hyperthermia. In one aspect, such combination therapies can advantageously utilize lower dosages of the administered therapeutic agents, thereby avoiding potential toxicities or complications associated with various monotherapies.

[0395] Pharmaceutical Composition In another aspect, the present disclosure provides a composition, e.g., a pharmaceutically acceptable composition, comprising a radiolabeled compound of Formula (I) (e.g., a compound of any one of embodiments 1-56), or a pharmaceutically acceptable salt thereof, and a radical scavenger, such as gentisic acid and / or ascorbic acid.

[0396] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: 177

[0013] The present invention provides a pharmaceutically acceptable composition comprising

[0014] [Lu]-compound 34, or a pharmaceutically acceptable salt thereof. In particular embodiments of this aspect, the composition further comprises a radical scavenger. In more particular embodiments of this aspect, the composition further comprises gentisic acid / acetate buffer, DTPA (diethylenetriaminepentaacetic acid), and sodium ascorbate.

[0397] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: 175 Lu]-Compound 34, or a pharmaceutically acceptable salt thereof.

[0398] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: 225 Ac]-Compound 37, or a pharmaceutically acceptable salt thereof.

[0399] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: 177

[0013] The present invention provides a pharmaceutically acceptable composition comprising

[0014] [Lu]-compound 37, or a pharmaceutically acceptable salt thereof. In particular embodiments of this aspect, the composition further comprises a radical scavenger. In more particular embodiments of this aspect, the composition further comprises gentisic acid / acetate buffer, DTPA (diethylenetriaminepentaacetic acid), and sodium ascorbate.

[0400] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: 175 Lu]-Compound 37, or a pharmaceutically acceptable salt thereof.

[0401] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: 225 Ac]-Compound 37, or a pharmaceutically acceptable salt thereof.

[0402] In another aspect, the present disclosure provides compositions, e.g., pharmaceutically acceptable compositions, comprising one or more, e.g., two, three, four, five, six, seven, eight, or more, FR-targeting compounds of the present disclosure, such as a radiolabeled compound of Formula (I) (e.g., a compound of any one of embodiments 1-56), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments of this aspect, the composition comprises an additional therapeutic agent, as described herein.

[0403] In another aspect, the FR-targeted compounds of the present disclosure, such as the compounds of Formula (I) (e.g., any one of the compounds of Embodiments 1 to 56) for diagnosis or treatment, can be provided by (1) a method for providing a labeled preparation containing a radiolabeled FR-targeted compound and (2) a method for providing a kit preparation containing the FR-targeted compound or a salt thereof. When the FR-targeted compound for diagnosis or treatment is provided as a labeled preparation, the preparation can be used directly for administration. When the kit preparation is used, the FR-targeted compound is labeled with the desired radiometal at the clinical site and then used for administration. The kit preparation can be provided in the form of an aqueous solution or a lyophilized preparation. The use of the kit preparation can eliminate the need for special purification steps, and the reaction solution can be prepared immediately before use as an administration solution by simply carrying out the reaction with the addition of a radiometal obtained from a generator regularly stored at the clinical site or a radiometal provided by a drug manufacturer separately from or in combination with the kit preparation.

[0404] In embodiments, the pharmaceutically acceptable carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (eg, by injection or infusion).

[0405] The compositions described herein may exist in a variety of forms.

[0406] In various embodiments, these include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0407] In one aspect, the composition is in the form of a solution for injection or infusion, hi certain embodiments, the method of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular).

[0408] In one embodiment, the composition is administered by intravenous infusion or injection, hi another embodiment, the composition is administered by intramuscular or subcutaneous injection.

[0409] The phrases "parenteral administration" and "administered parenterally," as used herein, mean modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0410] In one aspect, therapeutic compositions should be sterile and stable under the conditions of manufacture and storage.

[0411] In various embodiments, the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure.

[0412] In one embodiment, the composition is suitable for high antibody concentrations. Sterile injectable solutions can be prepared by incorporating the active compound I and additional therapeutic agents in the required amount in an appropriate solvent with one or a combination of the ingredients listed above, as required, followed by sterile filtration.

[0413] In one embodiment, the dispersion is prepared by incorporating the FR targeting compound of the present disclosure, for example, a compound of formula (I), and optionally any additional therapeutic agent, into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which produce a powder of the active ingredient and any additional desired ingredient from a previously sterile-filtered solution thereof.

[0414] In one aspect, the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0415] In another embodiment, prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0416] In certain embodiments, the composition is a bulk formulation. In other embodiments, the formulation is a lyophilized formulation, e.g., lyophilized or dried from a bulk formulation. In other embodiments, the formulation is a reconstituted formulation, e.g., reconstituted from a lyophilized formulation. In other embodiments, the formulation is a liquid formulation.

[0417] Other exemplary buffers that can be used in the formulations described herein include, but are not limited to, arginine buffer, citrate buffer, or phosphate buffer.Other exemplary carbohydrates that can be used in the formulations described herein include, but are not limited to, trehalose, mannitol, sorbitol, or combinations thereof.The formulations described herein may also contain an osmotic agent, such as sodium chloride, and / or a stabilizer, such as an amino acid (e.g., glycine, arginine, methionine, or combinations thereof).

[0418] The combinations, inhibitors, antagonists, or binding agents according to the present invention can be administered by a variety of methods known in the art, but for many therapeutic applications, the preferred route / method of administration is intravenous injection or infusion. For example, a FR therapeutic agent, such as a radiolabeled compound of Formula (I), or other therapeutic agent, can be administered by intravenous infusion.

[0419] As will be understood by those skilled in the art, the route and / or method of administration will vary depending on the desired results.In certain embodiments, the active compound can be prepared with a carrier that will prevent the compound from being released rapidly, such as a controlled-release formulation, including implants, transdermal patches, and microencapsulated delivery systems.In various embodiments, biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Many methods for preparing such formulations are generally known to those skilled in the art.See, for example, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0420] In certain embodiments, the combinations according to the present invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier. In another embodiment, any of the therapeutic agents described herein (and optionally other ingredients) may also be encapsulated in hard or soft shell gelatin compressed tablets or incorporated directly into the subject's diet. For oral therapeutic administration, the therapeutic agent may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. In one embodiment, to administer a therapeutic agent of the present disclosure by other than parenteral administration, it may be necessary to coat or co-administer the therapeutic agent with a material that prevents its inactivation. In another aspect, the therapeutic composition may be administered with a medical device known in the art.

[0421] Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, or multiple divided doses may be administered over a period of time, or the dose may be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. In one embodiment, parenteral compositions may be formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unitary doses for treatment, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. In various aspects, the specifications for the unit dosage forms of the present invention are dictated by and directly depend on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the technology of compounding such active compounds for treating subjects. [Example]

[0422] Abbreviation: DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 2-Nal = 3-(2-naphthyl)-alanine HFIP = hexafluoroisopropanol TIPS = Triisopropylsilane TFA = trifluoroacetic acid IPA = Isopropyl alcohol DMF = dimethylformamide DMSO = dimethyl sulfoxide DCM = dichloromethane TEA = triethylamine DIPEA = N,N-diisopropylethylamine FDRPMI or RPMI = Folate Deficiency Roswell Park Memorial Institute FCS = fetal calf serum

[0423] Chemical Examples The compounds of the present disclosure can be prepared as described in the Examples below. TFA-labile Wang resin is a standard support for batch synthesis of peptide acids following an Fmoc- / tBu-protection scheme. Fmoc-amino acids can be coupled to a 4-hydroxymethylphenoxyacetic acid linker in a manner that minimizes epimerization and dipeptide formation. Preloaded Wang resin (e.g., preloaded with N-α-Fmoc-protected amino acids) is a commercially available (e.g., from Sigma-Aldrich) high-quality support, allowing for direct start-up with automated protocols. Typically, the polymer matrix for preloaded Wang resin is polystyrene cross-linked with 1% DVB.

[0424] Example 1: Pte(N 10 -TFA)-Dap-OH(1) [ka] 1 was synthesized by solid phase peptide synthesis (SPPS) on Wang resin. In a peptide synthesis vessel, 1.10 g of N β -Boc-N α -Fmoc-L-2,3-diaminopropanoic acid resin (Fmoc-Dap(Boc)-resin, commercially available) (0.500 mmol, 1 equivalent) was added. A solution of 20% piperidine in dimethylformamide (DMF) (approximately 20 mL) for Fmoc deprotection was added. Argon was bubbled through the solution for 15 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 5 minutes, followed by venting (repeated twice). The resin was washed with DMF (approximately 20 mL x 3), followed by isopropyl alcohol (IPA, approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3). Next, 20 mL of DMF was added to the peptide synthesis vessel. Solid N 10 -(trifluoroacetyl)pteroic acid (Pte(TFA)-OH) was added to the reaction vessel immediately followed by the addition of 0.125 mL (2.00 mmol, 4 equiv.) of diisopropylethylamine ( iPr2NEt), followed by 520 mg (1.00 mmol, 2 equiv.) of benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP). Argon was bubbled through the solution for 1 h and then evacuated. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3). 25 mL of cleavage reagent (95% trifluoroacetic acid (TFA), 2.5% HO, 2.5% triisopropylsilane (TIPS)) was added to the peptide synthesis vessel, argon was bubbled through for 1 h, the vessel was evacuated, and this sequence was repeated with the cleavage reagent (10 mL for 15 min). The filtrate was concentrated under reduced pressure until approximately 10 mL remained. The product was triturated with 40 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 50 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum. 152 mg (62.5%) of the desired product was isolated as a yellow powder and used without further purification. LC / MS (ESI-QMS): m / z = 495.2 (M+H). + .

[0425] Example 2: [ka] Dissolve 25 mg (0.0506 mmol, 1.0 equiv.) of 1 in 0.0360 mL (0.202 mmol, 4 equiv.) of dimethyl sulfoxide (DMSO) in 0.500 mL of DMSO. iA solution of Pr₂NEt was added to the reaction mixture. 35 mg (0.0506 mmol, 1 equiv.) of S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (p-SCN-Bn-DOTA(H₄), commercially available) was added to the stirring reaction mixture. The reaction was monitored by LS / MS, and after complete consumption of the starting material 1, 0.016 mL (0.506 mmol, 10 equiv.) of hydrazine (NH₂NH₂) was added to the reaction mixture. The progress of the reaction was again monitored by LS / MS, and after complete deprotection of the TFA group, the reaction mixture was loaded onto a C₁₈ silica column and purified by reverse-phase chromatography (0–35% acetonitrile (ACN) in aqueous NH₄HCO₃ buffer (pH = 7)). 12 mg (25%) of the desired product was recovered as a yellow powder after lyophilization: LC / MS (ESI-QMS): m / z=950.57 (M+H) + .

[0426] Example 3: [ka] Dissolve 25 mg (0.0506 mmol, 1.0 equiv.) of 1 in 0.0360 mL (0.202 mmol, 4 equiv.) of DMSO in 0.500 mL of DMSO. iA solution of PrNEt was added to the reaction mixture. 39 mg (0.0506 mmol, 1 equiv.) of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester HPF6 TFA salt (DOTA(H3)-NHS, commercially available) was added to the stirring reaction mixture. The reaction was monitored by LS / MS, and after complete consumption of the starting material 1, 0.016 mL (0.506 mmol, 10 equiv.) of hydrazine (NH2NH2) was added to the reaction mixture. The progress of the reaction was again monitored by LS / MS, and after complete deprotection of the TFA group, the reaction mixture was loaded onto a C18 silica column and purified by reverse-phase chromatography (0–35% acetonitrile (ACN) in aqueous NH4HCO3 buffer (pH = 7 buffer)). 8 mg (20%) of the desired product was recovered as a yellow powder after lyophilization: LC / MS (ESI-QMS): m / z=785.20 (M+H) + .

[0427] Example 4: [ka] 100 mg (0.202 mmol, 1.0 equiv.) of 1 was added to a solution of 0.110 mL (0.809 mmol, 4 equiv.) of EtN in 2.02 mL of DMF. 170 mg (0.242 mmol, 1.2 equiv.) of 2-[1,4,7,10-tetraazacyclododecane-4,7,10-tris(t-butyl acetate)]-pentanedioic acid-1 t-butyl ester (DOTAGA(tBu4)-NHS, commercially available) followed by 126 mg (0.242 mmol, 1.2 equiv.) of PyBOP were added to the stirred reaction mixture. The reaction was monitored by LS / MS, and after complete consumption of starting material 1 (3 h), the reaction mixture was concentrated to dryness. 0.500 mL of CHCl was added to the crude residue and stirred vigorously. The solvent was removed under reduced pressure, and the previous step was repeated twice. The resulting residue was dissolved in a minimum amount of DMSO and loaded onto a C18 column. The product was purified by reverse-phase chromatography (10-80% ACN / 0.1% TFA) and lyophilized to give 152 mg (64%) of the desired product as a pale yellow powder: LC / MS (ESI-QMS): m / z = 1178.8 (M+H). + .

[0428] 0.200 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% TIPS) was added to 100 mg of 4 (0.0850 mmol, 1.0 equiv.). The reaction mixture was stirred overnight (approximately 19 h) at room temperature. The product was triturated in 10 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 10 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum. The resulting powder was dissolved in water, and potassium carbonate was added until the solution reached a pH of 10. The reaction mixture was stirred under argon for 1 h and analyzed by LC / MS for complete deprotection of the pteroate. The crude reaction mixture was loaded onto a C18 column. The product was purified by reverse-phase chromatography (0-30% ACN / 0.1% TFA). Fractions containing the desired product (analyzed by LC / MS) were concentrated until the solution became opaque. A small amount of DMSO was added until the solution became homogeneous. The solution was loaded onto a C18 column, purified by HPLC (0-30% ACN / NH4HCO3 (pH = 7) buffer), and lyophilized to give 22 mg (30% over two steps) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z = 857.4 (M+H). + .

[0429] Example 5: [ka] To a mixture of 1.00 g of N-benzyloxycarbonyl-L-glutamic acid 5-tert-butyl ester (Cbz-Glu(OtBu)-OH (commercially obtained), 2.964 mmol, 1 equiv.), 1.040 g of mono-Fmoc ethylenediamine hydrochloride (Fmoc-EDA (commercially obtained), 3.261 mmol, 1.1 equiv.), and 1.697 g of PyBOP (3.261 mmol, 1.1 equiv.) in 29.6 mL of DMF was added 1.163 mL of iPr2NEt (6.528 mmol, 2.2 equiv.) was added dropwise. The reaction progress was monitored by LC / MS; after 1 h, the starting material Cbz-Glu(OtBu)-OH was consumed. The reaction mixture was then concentrated under high vacuum. The residue was taken up in 50 mL of ethyl acetate (EtOAc) and 50 mL of brine. The solution was vigorously shaken, resulting in the formation of an emulsion. After the layers were separated, the organic layer was isolated and the extraction was repeated twice. The combined organic layers were dried over sodium sulfate (Na2SO4) and filtered. Celite was added to the filtrate, and the heterogeneous solution was concentrated to dryness. The resulting permeable Celite was loaded onto a silica column, and the product was purified by silica chromatography (5–85% EtOAc in petroleum ether). 1.28 g (72%) of the desired product was isolated as a white solid: LC / MS (ESI-QMS): m / z = 602.3 (M+H). + .

[0430] 84 mg of 10% palladium on carbon (Pd / C, 10% w / w, 0.0831 mmol, 0.1 equiv.) was added to a solution of 500 mg of 6 (0.831 mmol, 1.0 equiv.) in 20% ethyl alcohol in tetrahydrofuran (EtOH / THF) (8.3 mL) under argon. The headspace was evacuated and refilled with hydrogen gas twice. The reaction mixture was stirred under hydrogen for 2 hours. The reaction mixture was filtered through a pad of Celite and washed with ethanol. The filtrate was concentrated under reduced pressure and dried under high vacuum to give the desired product as a light brown solid. The crude residue from the previous reaction was dissolved in 8.3 mL of DMF. To the reaction mixture was added 0.326 mL of iPrNEt (1.828 mmol, 2.2 equiv.) and 407 mg of Pte(TFA)-OH (0.997 mmol, 1.2 equiv.) were added, followed by 518 mg of PyBOP (0.997 mmol, 1.2 equiv.). The reaction was monitored by LC / MS after the protected pteroic acid slowly went into solution. After stirring the reaction mixture for 4 h, the reaction mixture was concentrated to dryness. The residue was dissolved in a minimal amount of DMSO and loaded onto a C18 column. The product was purified by reverse-phase chromatography (10-85% ACN / HO) and lyophilized to give 364 mg (51% over two steps) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z = 858.3 (M+H). + .

[0431] 0.230 mL of diethylamine (EtNH) was added to a solution of 200 mg of 7 (0.233 mmol, 1.0 equiv.) in 2.10 mL of DMF. The reaction mixture was stirred under argon at room temperature for 1.5 h and concentrated under reduced pressure. The residue was co-evaporated with CHCl (1 mL × 3), dried under high vacuum for 30 min, and dissolved in anhydrous DMF (2.3 mL). To the reaction mixture, 0.0910 mL of i PrNEt (0.513 mmol, 2.2 equiv.) and 196 mg of 2-[1,4,7,10-tetraazacyclododecane-4,7,10-tris(t-butyl acetate)]-pentanedioic acid-1 t-butyl ester (DOTAGA(tBu4) (commercially obtained), 0.280 mmol, 1.2 equiv.) were added, followed by 145 mg of PyBOP (0.280 mmol, 1.2 equiv.). The reaction mixture was stirred for 4 h, after which the reaction mixture was concentrated to dryness. The residue was dissolved in a minimal amount of DMSO and loaded onto a C18 column. The product was purified by reverse-phase chromatography (5-65% ACN / 0.1% TFA) and lyophilized to give 165 mg (54%) of the desired product as a pale yellow powder: LC / MS (ESI-QMS): m / z = 1318.9 (M+H). + .

[0432] 0.200 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% TIPS) was added to 100 mg of 8 (0.0758 mmol, 1.0 equiv.). The reaction mixture was stirred overnight (approximately 19 h) at room temperature. The product was triturated in 10 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 10 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum. The resulting powder was dissolved in water, and potassium carbonate was added until the solution reached a pH of 10. The reaction mixture was stirred for 1 h and analyzed by LC / MS for complete deprotection of the pteroate. The crude reaction mixture was loaded onto a C18 column. The product was purified by reverse-phase chromatography (0-30% ACN / 0.1% TFA). Fractions containing the desired product (analyzed by LC / MS) were concentrated until the solution became opaque. A small amount of DMSO was added until the solution became homogeneous. The solution was loaded onto a C18 column, purified by HPLC (0-30% ACN / NH4HCO3 buffer (pH = 7)), and lyophilized to give 12 mg (13% over two steps) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z = 942.6 (M+H). + .

[0433] Example 6: [ka] 10 was synthesized by solid phase in 10 steps starting from Fmoc-Dap(Boc)-Wang-resin (Table 1). In a peptide synthesis vessel, 1.10 g of Fmoc-Dap(Boc)-R (0.500 mmol, 1 equiv.) was added.

[0434] [Table 1]

[0435] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step. For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 15 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 5 minutes before venting (2x). The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0436] Step B: Amino Coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 1 hour and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0437] Step C: Resin cutting The resin was washed with CHCl (approximately 20 mL × 3). 25 mL of cleavage reagent (95% TFA, 2.5% H2O, 2.5% TIPS) was added to the peptide synthesis vessel, bubbled with argon for 1 h, emptied, and repeated twice with cleavage reagent (10 mL for 15 min). The reaction mixture was concentrated under reduced pressure until 10 mL remained. The product was triturated with 40 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 50 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum.

[0438] Step D:N 10 TFA deprotection The resulting powder was dissolved in water and potassium carbonate was added until the pH of the solution reached 10. The reaction mixture was stirred under argon for 1 hour and analyzed by LC / MS for complete deprotection of the pteroate.

[0439] purification The crude reaction mixture was loaded onto a C18 column. The product was purified by reverse-phase chromatography (0-35% ACN / 0.1% TFA). Fractions containing the desired product (analyzed by LC / MS) were concentrated, frozen using a dry ice / acetone bath, and lyophilized to give 355 mg (51% over 12 steps) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z = 1390.8 (M+H). + .

[0440] Dissolve 50 mg (0.0360 mmol, 1.0 equiv) of 10 in 0.026 mL (0.144 mmol, 4 equiv) of DMF in 0.400 mL of DMF. i A solution of Pr2NEt was added. 27 mg (0.0360 mmol, 1 equiv.) DOTA(H3)-NHS was added to the stirring reaction mixture. The reaction was monitored by LC / MS, and after complete consumption of starting material 10, the reaction mixture was concentrated. 0.500 mL of CHCl2 was added to the crude residue and stirred vigorously. The solvent was removed under reduced pressure, and the previous step was repeated twice. The resulting solid was dissolved in a minimum amount of DMSO and loaded onto a C18 silica column. The product was purified by reverse-phase chromatography (0-30% ACN / pH 2 buffer). Fractions containing the desired product (analyzed by LC / MS) were concentrated until the solution became opaque. A small amount of DMSO was added until the solution became homogeneous. The solution was loaded onto a C18 column, purified by HPLC (0-30% ACN / NH4HCO3 buffer pH=7), and lyophilized to give 10 mg (15%) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z=1777.7 (M+H). + .

[0441] Example 7: [ka] 12 was synthesized by solid phase in 10 steps starting from Fmoc-Dap(Boc)-Wang-resin (Table 2). The procedure followed the same sequence as that for 10, except that Fmoc-Glu-OtBu was used instead of Fmoc-Asp-OtBu. 310 mg (44% over 12 steps) of the desired product was isolated as a yellow powder: LC / MS (ESI-QMS): m / z = 1404.7 (M+H). + .

[0442] [Table 2]

[0443] Dissolve 50 mg (0.0356 mmol, 1.0 equiv) of 12 in 0.025 mL (0.142 mmol, 4 equiv) of 12 in 0.400 mL of DMF. i A solution of PrNEt was added to the reaction mixture. 27 mg (0.0356 mmol, 1 equiv.) DOTA(H)-NHS was added to the stirring reaction mixture. The reaction was monitored by LC / MS, and after complete consumption of starting material 12, the reaction mixture was concentrated. 0.500 mL of CHCl was added to the crude residue and stirred vigorously. The solvent was removed under reduced pressure, and the previous step was repeated twice. The resulting solid was dissolved in a minimum amount of DMSO and loaded onto a C18 silica column. The product was purified by reverse-phase chromatography (0-30% ACN / 0.1% TFA). Fractions containing the desired product (analyzed by LC / MS) were concentrated until the solution became opaque. A small amount of DMSO was added until the solution became homogeneous. The solution was loaded onto a C18 column, purified by HPLC (0-30% ACN / NH4HCO3 buffer (pH = 7)), and lyophilized to give 12 mg (19%) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z = 1791.5 (M+H). + .

[0444] Example 8: [ka] 14 was synthesized by solid phase in six steps starting from Fmoc-Lys(N-4-methoxytrityl)-2-chlorotrityl-resin (Table 3). In a peptide synthesis vessel, 1.47 g of Fmoc-Lys(N-4-methoxytrityl)-2-chlorotrityl-resin (0.500 mmol, 1 equiv.) was added.

[0445] [Table 3]

[0446] Step A: Fmoc deprotection A solution of 20% piperidine in DMF (approximately 20 mL) for Fmoc deprotection was added. Argon was bubbled through the solution for 15 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 5 minutes, followed by venting (2x). The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0447] Step B: Amino Coupling Amino acid solution in DMF (approximately 20 mL), i PrNEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 1 h and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and finally with CHCl (approximately 20 mL x 3).

[0448] Step C: Mtt cutting Approximately 20 mL of 2% TFA in CHCl was added, and argon was bubbled through the solution for 5 minutes. Small amounts of CHCl were added to the reaction vessel to maintain the same volume even with vigorous bubbling. The yellow solution was then drained and repeated five times. The resin was washed with fresh CHCl until the filtrate remained clear. A 2% solution of TFA in CHCl was added once more. If the solution remained clear, the reaction mixture was drained and the next coupling step was carried out. If the solution turned yellow, the resin was washed with fresh CHCl until clear, and the process was repeated until a clear reaction solution was obtained. The resin was then washed with DMF (approximately 20 mL x 3).

[0449] Step D: Chelating Agent Coupling i Pr2NEt was added to a solution of DOTA(H3)-NHS (approximately 20 mL) in DMF in a peptide synthesis vessel. Argon was bubbled through the solution for 1 h and then evacuated. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and finally CHCl2 (approximately 20 mL x 3).

[0450] Step E: Resin cutting 25 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% TIPS) was added to the peptide synthesis vessel, bubbled with argon for 1 hour, evacuated, and repeated twice with cleavage reagent (10 mL for 15 minutes). The reaction mixture was concentrated under reduced pressure until 10 mL remained. The product was triturated with 40 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 50 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum.

[0451] Step F:N 10 TFA deprotection The resulting powder was dissolved in water and potassium carbonate was added until the pH of the solution reached 10. The reaction mixture was stirred under argon for 1 hour and analyzed by LC / MS for complete deprotection of the pteroate.

[0452] purification The crude reaction mixture was loaded onto a C18 column. The product was purified by reverse-phase chromatography (0-30% ACN / 0.1% TFA). Fractions containing the desired product (analyzed by LC / MS) were concentrated to an opaque solution, frozen (dry ice / acetone bath), and lyophilized to give 255 mg (62%) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z = 827.6 (M+H). + .

[0453] Example 9: [ka] Dissolve 200 mg (0.404 mmol, 1.0 equiv) of 1 in 0.173 mL (0.970 mmol, 2.4 equiv) of DMF in 4.04 mL of DMF. i To the stirred reaction mixture was added 199 mg (0.485 mmol, 1.2 equiv.) of Fmoc-Asp(OtBu)-OH (commercially obtained), followed by 252 mg (0.485 mmol, 1.2 equiv.) of PyBOP. The reaction was monitored by LC / MS, and after complete consumption of starting material 1 (1 h), the product was triturated in 12 mL of 1 M aqueous hydrochloric acid at 0 °C and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 12 mL of aqueous HCl and centrifuging. The pellet was frozen in a dry ice / acetone bath and lyophilized overnight. 275 mg (77%) of the resulting pale yellow powder was isolated and used without further purification. LC / MS (ESI-QMS): m / z = 888.8 (M+H). + .

[0454] 0.282 mL of diethylamine (EtNH) was added to a solution of 250 mg of 15 (0.282 mmol, 1.0 equiv.) in 2.54 mL of DMF. The reaction mixture was stirred at room temperature under argon for 1 h and then concentrated under reduced pressure. The residue was coevaporated with CHCl (1 mL × 3), dried under high vacuum for 30 min, and dissolved in anhydrous DMF (2.3 mL). 0.121 mL (0.677 mmol, 2.4 equiv.) of i After the addition of PrNEt, 237 mg (0.338 mmol, 1.2 equiv.) of DOTAGA(tBu3) (commercially obtained) and 176 mg (0.338 mmol, 1.2 equiv.) of PyBOP were added. The reaction was monitored by LS / MS, and after complete consumption of starting material 15, the reaction mixture was concentrated. 1.0 mL of CHCl2 was added to the crude residue and stirred vigorously. The solvent was removed under reduced pressure, and the previous step was repeated twice. The resulting solid was dissolved in a minimal amount of DMSO and loaded onto a C18 silica column. The product was purified by reverse-phase chromatography (0–35% ACN / 0.1% TFA). Fractions containing the desired product (analyzed by LC / MS) were concentrated until the solution was opaque, frozen, and lyophilized to give 120 mg (40%) of the desired product as a pale yellow powder: LC / MS (ESI-QMS): m / z=1052.3 (M+H). + .

[0455] 0.200 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% TIPS) was added to 100 mg of 16 (0.0951 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 5.5 hours. The product was triturated in 10 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 10 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum. The resulting powder was dissolved in water, and potassium carbonate was added until the solution reached a pH of 10. The reaction mixture was stirred for 1 hour and analyzed by LC / MS for complete deprotection of the pteroate. The crude reaction mixture was loaded onto a C18 column. The product was purified by reverse-phase chromatography (0-35% ACN / 0.1% TFA). Fractions containing the desired product (analyzed by LC / MS) were concentrated until the solution became opaque. A small amount of DMSO was added until the solution became homogeneous. The solution was loaded onto a C18 column, purified by reverse-phase chromatography (0-20% ACN / NH4HCO3 buffer (pH = 7)), and lyophilized to give 9 mg (11% over two steps) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z = 900.7 (M+H). + .

[0456] Example 10: [ka] Dissolve 200 mg (0.404 mmol, 1.0 equiv) of 1 in 0.173 mL (0.970 mmol, 2.4 equiv) of DMF in 4.04 mL of DMF. iTo the stirred reaction mixture was added 199 mg (0.485 mmol, 1.2 equiv.) of Fmoc-Asp-OtBu (commercially obtained), followed by 252 mg (0.485 mmol, 1.2 equiv.) of PyBOP. The reaction was monitored by LC / MS, and after complete consumption of starting material 1 (1 h), the product was triturated in 12 mL of 1 M aqueous hydrochloric acid at 0 °C and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 12 mL of aqueous HCl and centrifuging. The pellet was frozen in a dry ice / acetone bath and lyophilized overnight. 255 mg (71%) of the resulting pale yellow powder was isolated and used without further purification. LC / MS (ESI-QMS): m / z = 888.6 (M+H). + .

[0457] 0.282 mL of diethylamine (EtNH) was added to a solution of 250 mg of 18 (0.282 mmol, 1.0 equiv.) in 2.54 mL of DMF. The reaction mixture was stirred at room temperature under argon for 1 h and then concentrated under reduced pressure. The residue was coevaporated with CHCl (1 mL × 3), dried under high vacuum for 30 min, and dissolved in anhydrous DMF (2.3 mL). 0.121 mL (0.677 mmol, 2.4 equiv.) of iAfter the addition of PrNEt, 237 mg (0.338 mmol, 1.2 equiv.) of DOTAGA(tBu3) (commercially obtained) and 176 mg (0.338 mmol, 1.2 equiv.) of PyBOP were added. The reaction was monitored by LS / MS, and after complete consumption of starting material 18, the reaction mixture was concentrated. 1.0 mL of CHCl was added to the crude residue and stirred vigorously. The solvent was removed under reduced pressure, and the previous step was repeated twice. The resulting solid was dissolved in a minimal amount of DMSO and loaded onto a C18 silica column. The product was purified by reverse-phase chromatography (0–35% ACN / 0.1% TFA). Fractions containing the desired product (analyzed by LC / MS) were concentrated until the solution was opaque, frozen, and lyophilized to give 112 mg (38%) of the desired product as a pale yellow powder: LC / MS (ESI-QMS): m / z=1052.3 (M+H). + .

[0458] 0.200 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% TIPS) was added to 90 mg of 19 (0.0856 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 5.5 h. The product was triturated in 10 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 10 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum. The resulting powder was dissolved in water, and potassium carbonate was added until the solution reached a pH of 10. The reaction mixture was stirred for 1 h and analyzed by LC / MS for complete deprotection of the pteroate. The crude reaction mixture was loaded onto a C18 column. The product was purified by reverse-phase chromatography (0-35% ACN / pH = 2 buffer). Fractions containing the desired product (analyzed by LC / MS) were concentrated until the solution became opaque. A small amount of DMSO was added until the solution became homogeneous. The solution was loaded onto a C18 column, purified by reverse-phase chromatography (0-20% ACN / NH4HCO3 buffer (pH = 7)), and lyophilized to give 8 mg (10% over two steps) of the desired product as a yellow powder: LC / MS (ESI-QMS): m / z = 900.7 (M+H). + .

[0459] Example 11: [ka] Folate spacer 21 was synthesized by standard Fmoc-solid phase peptide synthesis (SPPS) techniques following the general procedure outlined for 10 from Fmoc-L-Lys(Boc)-Wang resin using the following amounts of material:

[0460] [Table 4]

[0461] As described in the general procedure, 2 equivalents of PyBOP and 4 equivalents ofi Each of the carboxylic acids listed above was coupled to the growing peptide chain using PrNEt. PEG coupling was carried out overnight without the addition of PyBOP. After cleavage, UPLC analysis showed a mixture of the desired compound and spacer without the PEG moiety. The crude material was purified by C18 silica reverse-phase column chromatography (0.1% TFA and ACN as eluents) to give 20 mg of the desired product after lyophilization. 1 H NMR(500MHz,DMSO-d6 / D2O):δ 8.64(s,1H),7.62(d,2H,J=8.5Hz),6.62(d,2H,J=8.5Hz),4.47(s,2H),4.25(m,3H),4.18(dd,1H,J=5.5,8Hz),3.91(s,3H ),3.65-3.3(m),3.16,(m,3H),2.74(t,2H,J=8Hz),2.3-2.15(m,4H),2.02(m,1H),1.9-1.6(m,6H),1.5(m,2H),1.3(m,2H).

[0462] Example 12: [ka] Folic acid spacer 21 (5 mg, assumed to be 0.0012 mmol) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester HPF6 TFA salt (DOTA(H3)-NHS (commercially obtained), 4.7 mg, 4 equivalents) were dissolved in ACN (125 μL). To this solution was added triethylamine (TEA, 5 mL, 29 equivalents). The reaction was stirred for 2 hours. The reaction was diluted with HO and loaded onto a C18 silica reverse-phase column (0.1% TFA and ACN eluent) to yield 2.9 mg of the conjugate after lyophilization. 1H NMR(500MHz,DMSO-d6 / D2O):δ 8.63(s,1H),7.63(d,2H,J=8.5Hz),6.63(d,2H,J=8.5Hz),4.48(s,2H),4.3-4.1(m,4H),3.92(s,3H), 3.9-3.3(m),3.2-2.8(m,22H),2.3-2.2(m,4H),2.05(m,1H),1.95-1.6(m,6H),1.4(m,2H),1.3(m,2H).

[0463] Example 13: [ka] 23 was synthesized by standard Fmoc-SPPS techniques following the general procedure outlined for 14 from Fmoc-L-Lys(Mtt)-Wang resin using the following materials:

[0464] [Table 5]

[0465] Unless otherwise noted, 2 equivalents of PyBOP and 4 equivalents of i PrNEt was used for each coupling step. The crude material was purified by C18 silica reverse-phase column chromatography (0.1% TFA and ACN as eluents) to give 15 mg of the desired product after lyophilization. LC / MS (ESI-QMS): m / z = 1163.6 (M + H). + , calculated m / z = 1163.6 1H NMR(500MHz,DMSO-d6 / D2O):δ 8.68(s,1H),7.81(d,1H,J=7Hz),7.74(m,2H),7.62(m,3H),7.4(m,2H),7.32(d,1H,J=8.5Hz),6.58(d,2H,J=8.5Hz),4.43(m,3H),4. 16(t,1H,J=7.5Hz),3.5-2.5(m,27H),1.97(bt,1H),1.7-1.45(m,6H),1.38(d,1H,J=9.5Hz),1.35-0.9(m,8H),0.75(t,2H,J=12Hz).

[0466] Example 14: [ka] 24 (5.0 mg, 0.0067 mmol) was dissolved in DMSO (700 μL) and TEA (9.3 μL, 10 equiv.) followed by 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide HPF6 TFA salt (DOTA-maleimide (commercially obtained), 7.4 mg, 1.4 equiv.) in DMSO (500 μL). The reaction was stirred for 1 h. The reaction was loaded directly onto a C18 silica reverse-phase column (0.1% TFA and ACN eluent) to give 7.5 mg of product after lyophilization. LC / MS (ESI-QMS): m / z = 1272.1 (M+H). + , calculated m / z = 1272.5 1 H NMR(500MHz,DMSO-d6 / D2O):δ 8.63(s,1H),7.62(d,2H,J=8.5Hz),6.63(d,2H,J=8.5Hz),4.63(dd,1H,J=6.5,14Hz),4.5-4.4(m,3H),4.34(dd,1H,J=5,10Hz),4 .00(m,2H),3.81(t,2H,J=7.5Hz),3.45-3.0(m,22H),2.91(m,1H),2.72(m,1H),2.22(bt,2H,J=7.5Hz),2.10(m,1H),1.88(m,1H).

[0467] Example 15: [ka] 26 was synthesized by standard Fmoc-SPPS techniques following the general procedure outlined for 14 from Fmoc-L-Lys(Mtt)-Wang resin using the following materials:

[0468] [Table 6]

[0469] 2 equivalents of PyBOP and 4 equivalents of i PrNEt was used for each coupling step. After standard resin cleavage, deprotection of the DOTAGA-associated tert-butyl ester was achieved by heating the cleavage solution to 35°C for 2 hours. The crude material was purified by C18 silica reverse-phase column chromatography (0.1% TFA and ACN as eluent) to give 9 mg of clean product and 7 mg of mixed fractions. LC / MS (ESI-QMS): m / z = 1235.5 (M+H). + , calculated m / z = 1235.6 1 H NMR (500MHz, DMSO-d6 / D2O): δ 8.58(s,1H),7.78(d,1H,J=8Hz),7.75(t,2H,J=15Hz),7.61(m,3H),7.39(m,2H),7.31(d,1H,J=8Hz).

[0470] Example 16: Pte(N 10 -TFA)-γGlu-EDA-NH 2 (27) [ka] 27 was synthesized from 1,2-diaminoethane trityl resin by standard Fmoc-SPPS techniques as described in the general synthetic procedure outlined for 10.

[0471] [Table 7]

[0472] In a peptide synthesis vessel, 1,2-diaminoethane trityl resin (0.285 g, 0.182 mmol) was placed and washed with DMF (3 × 10 ml). The initial Fmoc deprotection was carried out using 20% ​​piperidine in DMF (3 × 10 ml) for 10 minutes per cycle. This was followed by washing with DMF (3 × 10 ml) and IPA (3 × 10 ml), and a Kaiser test was performed to determine reaction completion. After another DMF wash (3 × 10 ml), the amino acid solution in DMF (2.0 equivalents), PyBOP (2.0 equivalents), and i PrNEt (3.0 equiv.) was added to the vessel, and the solution was bubbled with argon for 1 hour. The coupling solution was filtered, the resin washed with DMF (3 × 10 ml) and IPA (3 × 10 ml), and a Kaiser test was performed to assess reaction completion. The above process was carried out sequentially for additional couplings. Resin cleavage was carried out with 1,1,1,3,3,3 hexafluoro-2-propanol (10 ml) poured onto the resin and bubbled with argon for 30 minutes before filtering into a clean flask. Two further cleavage steps were carried out sequentially with fresh cleavage cocktail for 10 minutes each. The combined filtrate was concentrated under reduced pressure, and the crude residue was recovered to give the amine (0.105 g, 90%). LC / MS (ESI-QMS): m / z = 636.4 (M+H). + , calculated m / z = 635.6 1 H NMR (500MHz DMSO-d6) central signals: δ 8.49(s,1H),7.78(d,2H),7.45(d,2H),5.05(s,2H),1.32(s,9H).

[0473] Example 17: [ka] In a dry flask, 27 (102 mg, 0.161 mmol, 1.0 equiv.), DOTAGA(tBu4) (commercially obtained, 169 mg, 0.242 mmol, 1.5 equiv.), and PyBOP (168 mg, 0.323 mmol, 2.0 equiv.) were dissolved in DMF (5 ml) under argon. i PrNEt (0.12 ml, 0.645 mmol, 4 equiv.) was added to the solution and stirred for an additional 1 h. The reaction was monitored by LCMS until completion and purified using C18 silica reverse phase column chromatography (NHHCO (pH=7) and ACN eluent) to give N 10 The N-TFA protected conjugate was obtained. 10 The -TFA protected conjugate was dissolved in a solution of Na2CO3 and N 10 -TFA deprotection was monitored. Upon completion of the reaction, the deprotected amine was isolated using a C18 silica reverse-phase column and lyophilized. Further deprotection of the t-butyl ester was carried out by dissolving the conjugate in a solution of TFA and stirring for 1 hour. Upon complete deprotection, the reaction was concentrated under reduced pressure and purified using C18 reverse-phase silica to give conjugate 28 (12 mg, 8%). LC / MS (ESI-QMS): m / z = 942.4 (M + H). + , calculated m / z=941.9

[0474] Example 18: [ka] To a solution of 29 (25.5 mg, 0.053 mM) and tetramethylguanidine (TMG, 0.007 mL, 0.053 mM) in DMSO (2.0 mL) was added DOTA-benzyl isocyanate (commercially obtained, 34.98 mg, 0.063 mM) and iPrNEt (0.046 mL, 0.264 mM) was added. The resulting homogeneous solution was stirred under argon at ambient temperature for 1 h. LCMS analysis confirmed product formation. The reaction mixture was directly loaded onto preparative HPLC (mobile phase A = 50 mM ammonium bicarbonate, pH = 7.0. B = ACN. Method: 0 to 30% B in 25 min) for purification. Fractions containing the desired product were collected, combined, and lyophilized to give conjugate compound 30 (37.0 mg) as a yellow solid. LC / MS (ESI-QMS): m / z = 1035.8 (M+H). + , calculated m / z = 1035.4

[0475] Example 19: [ka] To a solution of pyridyldithioethylamine hydrochloride (commercially obtained, 10.8 mg, 0.049 mM) and iPr2NEt (0.130 mL, 0.730 mM) was added p-SCN-Bn-DOTA(H4) (commercially obtained, 50.00 mg, 0.073 mM) in portions over 15 min. The reaction mixture was stirred for 1 h. LCMS analysis confirmed the formation of the product. The reaction mixture was directly loaded onto preparative HPLC for purification (mobile phase A = 0.1% TFA in water, pH = 2.0. B = ACN. Method: 1 to 50% B in 25 min). Fractions containing the desired product were collected, combined, and lyophilized to give compound 31 (16.0 mg). LC / MS (ESI-QMS): m / z = 760.3 (M + Na). + , calculated m / z = 760.2

[0476] Example 20: [ka] A solution of 32 (20.8 mg, 0.022 mM) in DMSO (2.0 ml) was added with DOTA derivative 31 (16 mg, 0.022 mM) and iPrNEt (0.037 ml, 0.22 mM) was added. The resulting homogeneous solution was stirred under argon at ambient temperature for 1 h. LCMS analysis confirmed product formation. The reaction mixture was directly loaded onto preparative HPLC (mobile phase A = 0.1% TFA in water, pH = 2.0. B = ACN. Method: 0-30% B in 25 min) for purification. Fractions containing the desired product were collected, combined, and lyophilized to give conjugate 33 (7.5 mg) as a yellow solid. LC / MS (ESI-QMS): m / z = 779.9 (M+2H). 2+ , calculated m / z = 779.8

[0477] N-α-pteroyl-lysine-based DOTA conjugates: Example 21: Synthesis of Pte-Lys(β-Asp-2-Nal-Gly-DOTA)-OH (Compound 34): 2,2',2''-(10-((3S,11S,14S)-1-(4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)phenyl)-3,11-dicarboxy-14-(naphthalen-2-ylmethyl)-1,9,13,16,19-pentaoxo-2,8,12,15,18-pentaazaicosan-20-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid. [ka] Compound 34 was synthesized by solid phase in seven steps starting from Fmoc-Lys(N-4-methoxytrityl)-Wang-resin (Table 8).

[0478] [Table 8]

[0479] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step (in addition to Mtt deprotection using 25% HFIP in CHCl). For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 10 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 10 minutes before venting (2×). The resin was washed with DMF (approximately 20 mL × 3), followed by IPA (approximately 20 mL × 3), and then washed again with DMF (approximately 20 mL × 3).

[0480] Procedure B: Mtt cleavage Approximately 20 mL of 25% HFIP in CHCl was added, and argon was bubbled through the solution for 10 minutes. Small amounts of CHCl were added to the reaction vessel to maintain the same volume even with vigorous bubbling. The yellow solution was then drained and repeated five times. The resin was washed with fresh CHCl until the filtrate remained clear. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then again with DMF (approximately 20 mL x 3).

[0481] Step C: Amino acid coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 2 hours and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0482] Step D: Resin cutting The resin was washed with MeOH (approximately 20 mL × 3) and dried under a stream of argon. 25 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% Triisopropylsaline) was added to the peptide synthesis vessel, bubbled with argon for 1 h, emptied, and repeated with cleavage reagent (10 mL × 2 for 5 min). The reaction mixture was concentrated under reduced pressure until 10 mL remained. The product was triturated in 25 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 25 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum.

[0483] Step E: N in pteroic acid 10 -TFA group deprotection and purification The crude precipitate was suspended in water. 20% Na2CO3 was added until the pH of the solution reached 9.5. The clear solution was stirred for 1 h, and LCMS analysis confirmed the formation of the product. The pH of the solution was adjusted to 6.5 using 1N HCl and loaded onto a C18 column. The desired product was purified by reverse-phase chromatography (5-50% acetonitrile in 50 mM ammonium bicarbonate buffer at pH 7.0). The acetonitrile was evaporated under reduced pressure, and the remaining aqueous buffer solution was frozen and removed by lyophilization. [ka] LCMS(ESI):[M+H] + =C 55 H 70 N 15 O 16 Calculated value: 1196.50; measured value: 1196.7 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.62(s,1H),7.78(m,2H),7.70(d,J=9Hz,1H),7.68(s,1H),7.60(d,J=9Hz,2H),7.39(m,1H),7.38(m,2H),6.61(d,J=8.5Hz,2H),4.46(s,2H).

[0484] The above SPPS procedure was used to prepare the DOTA conjugate below.

[0485] Example 22: Fmoc-Tyr(O-benzyloxycarbonylmethyl)-O t Synthesis of Bu (compound 35): [ka] Fmoc-Tyr-O in dry acetone (10 mL) t To a solution of Bu (commercially obtained, 1.38 g, 3.0 mM) was added potassium carbonate (1.24 g, 9.0 mM) and stirred for 5 minutes. Bromobenzyl acetate (commercially obtained, 0.52 mL, 3.3 mM) was added. The reaction was stirred at room temperature for 3 hours, and LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The reaction mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed with water (2x) and brine. The organic layer was dried over Na2SO4, concentrated, and purified by combi-flash chromatography (0-100% EtOAc in petroleum ether) to give compound 35. LCMS(ESI):[M+H] + =C 37 H 38 Calculated value for NO7: 608.26; Measured value: 608.25 1H NMR(500MHz,CDCl3):δ 7.70(d,J=7.5Hz,2H),7.58(t,J1=6.0Hz,J2=6.5Hz,2H),7.36(m,9H),7.06(d,J=8.5Hz,2H) ,6.82(d,J=9.0Hz,2H),5.26(d,J=8.5Hz,1H),5.24(s,2H),4.63(s,2H),4.51(ABq,J1=13.5H z,J2=6.0Hz,5.5Hz,1H),4.45(dd,J1=10.5Hz,J2=7.0Hz,7.5Hz,1H),4.34(dd,J1=10.75Hz, J2=7.0Hz,7.5Hz,1H),4.21(t,J1=6.5Hz,J2=7.0Hz,1H),3.04(d,J=6.0Hz,2H),1.43(s,9H).

[0486] Example 23: Fmoc-Tyr(O-carboxymethyl)-O t Synthesis of Bu (compound 36): [ka] To a solution of compound 35 (0.40 g, 0.66 mM) in ethyl acetate (30 mL), 10% Pd / C (0.15 g) was added and stirred under a H atmosphere (balloon) for 15 minutes. LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The reaction mixture was filtered, concentrated, and dried to give compound 36. The material was used directly for the subsequent solid-phase coupling reaction. LCMS(ESI):[M+Na] + =C 30 H 31 Calculated value for NO7Na: 540.21; Measured value: 540.59 1H NMR(500MHz,CDCl3):δ 7.77(d,J=7.0Hz,2H),7.58(t,J1=7.0Hz,J2=7.5Hz,2H),7.41(t,J1=7.5Hz,J2=7.5Hz,2H),7.29 - 7.35(m,2H),7.08(d,J=8.0Hz,2H),6.84(d,J=8.0Hz,2H),5.38(d,J=8.0 Hz,1H),4.63(s,2H),4.53(ABq,J1=14.0Hz,J2=6.0Hz,1H),4.45(dd,J1=1 0.75Hz,J2=7.0Hz,7.5Hz,1H),4.35(dd,J1=11.0Hz,J2=7.0Hz,1H),4.21( t,J1=6.5Hz,J2=7.5Hz,1H),2.75-3.12(m,2H),1.43(s,6H),1.39(s,3H).

[0487] Example 24: Pte-Lys(DOTA-Gly-Tyr(O-carbonylmethyl)-OH)—OH (Compound 37): 2,2′,2″-(10-(2-((2-(((S)-2-(4-(2-(((S)-5-(4-(((2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl)amino)benzamido)-5-carboxypentyl)amino)-2-oxoethoxy)phenyl)-1-carboxyethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid. [ka] [ka] Compound 37 was synthesized by solid phase in six steps starting from Fmoc-Lys(N-4-methoxytrityl)-Wang-resin.

[0488] [Table 9]

[0489] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step (in addition to Mtt deprotection using 25% HFIP in CHCl). For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 10 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 10 minutes before venting (2×). The resin was washed with DMF (approximately 20 mL × 3), followed by IPA (approximately 20 mL × 3), and then washed again with DMF (approximately 20 mL × 3).

[0490] Procedure B: Mtt cleavage Approximately 20 mL of 25% HFIP in CHCl was added, and argon was bubbled through the solution for 10 minutes. Small amounts of CHCl were added to the reaction vessel to maintain the same volume even with vigorous bubbling. The yellow solution was then drained and repeated five times. The resin was washed with fresh CHCl until the filtrate remained clear. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then again with DMF (approximately 20 mL x 3).

[0491] Step C: Amino acid coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 2 hours and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0492] Step D: Resin cutting The resin was washed with MeOH (approximately 20 mL × 3) and dried under a stream of argon. 25 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% Triisopropylsaline) was added to the peptide synthesis vessel, bubbled with argon for 1 h, emptied, and repeated with cleavage reagent (10 mL × 2 for 5 min). The reaction mixture was concentrated under reduced pressure until 10 mL remained. The product was triturated in 25 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 25 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum.

[0493] Step E: N in pteroic acid 10 -TFA group deprotection and purification The crude precipitate was suspended in water. 20% Na2CO3 was added until the pH of the solution reached 9.5. The clear solution was stirred for 1 h, and LCMS analysis confirmed the formation of the product. The pH of the solution was adjusted to 6.5 using 1N HCl and loaded onto a C18 column. The desired product was purified by reverse-phase chromatography (5-50% acetonitrile in 50 mM ammonium bicarbonate buffer at pH 7.0). The acetonitrile was evaporated under reduced pressure, and the remaining aqueous buffer solution was frozen and removed by lyophilization. [ka] LCMS(ESI):[M+H] + =C 49 H 65 N 14 O 16 Calculated value: 1105.46; measured value: 1105.3 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.61(s,1H),7.61(d,J=9Hz,2H),7.08(d,J=8Hz,2H),6.74(d,J=8.5Hz,2H),6.61(d,J=8.5Hz,2H),4.48(s,2H),4.31(s,2H).

[0494] Examples 25-31 are synthesized using similar procedures as described in the above examples using the appropriate starting materials.

[0495] Example 25: Pte-Lys(DOTA-Tyr(O-carbonylmethyl)-OH)-OH (Compound 38): [ka] LCMS(ESI):[M+H] + =C 47 H 62 N 13 O 15 Calculated value: 1048.44; measured value: 1048.5 Selected Data 1 H NMR (500MHz, DMSO-d6, D2O): δ 8.60(s,1H),7.58(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),6.78(d,J=9.0Hz,2H),6.54(d,J=9.0Hz,2H),4.31(s,2H).

[0496] Example 26: Pte-Lys(DOTA-(Tyr(O-carbonylmethyl)-OH) 2 )-OH (compound 39): [ka] LCMS(ESI):[M+H] + =C 58 H 73 N 14 O 19 Calculated value: 1269.51; measured value: 1269.5 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.60(s,1H),7.58(d,J=8.0Hz,2H),7.06(d,J=8.5Hz,2H),7.00(d,J=8.0Hz,2H),6.71(d,J=8. 5Hz,2H),6.69(d,J=9.5Hz,2H),6.61(d,J=8.0Hz,2H),4.48(s,2H),4.36(s,2H),4.29(s,2H).

[0497] Example 27: Pte-Lys(2-Nal-Gly-DOTA)-OH (Compound 40): [ka] LCMS(ESI):[M+H] + =C 51 H 65 N 14 O 13 Calculated value: 1081.48; measured value: 1081.6 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.59(s,1H),7.74(m,2H),7.65(d,J=9.0Hz,2H),7.62(d,J=8.5Hz,2H),7.38(m,2H), 7.30(d,J=8.5Hz,1H),6.60(d,J=9.0Hz,2H),4.44(s,2H),4.35(m,1H),4.16(m,1H).

[0498] Example 28: Pte-Lys(β-Asp-2-Nal-DOTA)-OH (compound 41): [ka] LCMS(ESI):[M+H] + =C 53 H 67 N 14 O 15 Calculated value: 1139.48; measured value: 1139.70 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.61(s,1H),7.77(dd,J1=7.5Hz,J2=7.0Hz,2H),7.73(d,J=8.5Hz,1H),7.60(s,1H),7. 59(d,J=8.5Hz,2H),7.39(m,2H),7.31(d,J=7.5Hz,1H),6.61(d,J=8.5Hz,2H),4.67(br s,1H),4.46(s,2H),4.40(br s,1H),4.16(dd,J1=7.0Hz,J2=6.5Hz,1H).

[0499] Example 29: Pte-Lys(β-Asp-2-Nal-2-Nal-DOTA)-OH (compound 42): [ka] LCMS(ESI):[M+H] + =C 66 H 78 N 15 O 16 Calculated value: 1336.57; measured value: 1336.70 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.62(s,1H),7.87(br s,1H),7.80(m,4H),7.75-7.50(m,2H),7.64(d,J=8.5Hz,2H),7.50-7.35(m,6H),7.17(br s,1H),6.62(d,J=8.5Hz,2H),4.46(s,4H),4.31(br s,1H),4.23(t,J=6.5Hz,1H).

[0500] Example 30: Pte-Lys(β-Asp-4-Br-Phe-Gly-DOTA)-OH (Compound 43): [ka] LCMS(ESI):[M+H] + =C 51 H 67 BrN 15 O 16 Calculated value: 1224.40; Measured value: 1224.40 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.62(s,1H),7.58(d,J=8.5Hz,2H),7.31(d,J=8.0Hz,2H),7.14(d,J=8.5Hz,2H),6.62(d,J=8.5Hz,2H),4.46(s,2H) ,4.29(dd,J1=9.0Hz,J2=5.0Hz,1H),4.19(dd,J1=10.5Hz,J2=4.0Hz,1H),4.13(dd,J1=8.0Hz,J2=4.5Hz,5.5Hz,1H).

[0501] Example 31: Pte-Lys(Phe-Ala-Ser-Phe-Gly-Pro-Pro-Gly-DOTA)-OH (Compound 44): [ka] LCMS(ESI):[M+H] + =C 74 H 99 N 20 O 20 Calculated value: 1587.73; measured value: 1587.70 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.60(s,1H),7.59(d,J=9.0Hz,2H),7.23-7.07(m,10H),6.60(d,J=9.0Hz,2H),4.45 (s,2H),4.51-4.42(m,1H),4.37-4.17(m,4H),4.02-3.94(m,1H),3.93-3.85(m,1H).

[0502] N-ε-pteroyl-lysine-based DOTA conjugates: Example 32: Synthesis of DOTA-Gly-Lys(Pte)-OH (Compound 45): [ka] Compound 45 was synthesized by solid phase in five steps starting from Fmoc-Lys(N-4-methoxytrityl)-Wang-resin (Table 9).

[0503] [Table 10]

[0504] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step (in addition to Mtt deprotection using 25% HFIP in CHCl). For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 10 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 10 minutes before venting (2×). The resin was washed with DMF (approximately 20 mL × 3), followed by IPA (approximately 20 mL × 3), and then washed again with DMF (approximately 20 mL × 3).

[0505] Procedure B: Mtt cleavage Approximately 20 mL of 25% HFIP in CHCl was added, and argon was bubbled through the solution for 10 minutes. Small amounts of CHCl were added to the reaction vessel to maintain the same volume even with vigorous bubbling. The yellow solution was then drained and repeated five times. The resin was washed with fresh CHCl until the filtrate remained clear. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then again with DMF (approximately 20 mL x 3).

[0506] Step C: Amino acid coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 2 hours and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0507] Step D2: Cutting the resin The resin was washed with MeOH (approximately 20 mL × 3) and dried under a stream of argon. 25 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% Triisopropylsaline) was added to the peptide synthesis vessel, bubbled with argon for 1 hour, emptied, and repeated with cleavage reagent (10 mL × 2 for 5 minutes). The filtrate was stirred under argon at 35 °C for 2 hours. The reaction mixture was concentrated under reduced pressure until 10 mL remained. The product was triturated in 25 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 25 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum.

[0508] Step E: N in pteroic acid 10 -TFA group deprotection and purification The crude precipitate was suspended in water. 20% Na2CO3 was added until the pH of the solution reached 9.5. The clear solution was stirred for 1 h, and LCMS analysis confirmed the formation of the product. The pH of the solution was adjusted to 6.5 using 1N HCl and loaded onto a C18 column. The desired product was purified by reverse-phase chromatography (5-50% acetonitrile in 50 mM ammonium bicarbonate buffer at pH 7.0). The acetonitrile was evaporated under reduced pressure, and the remaining aqueous buffer solution was frozen and removed by lyophilization. [ka] LCMS(ESI):[M+H] + =C 38 H 54 N 13 O 12 Calculated value: 884.39; measured value: 884.406 Selected Data 1H NMR (500MHz, DMSO-d6, D2O): δ 8.61(s,1H),7.56(d,J=9.0Hz,2H),6.59(d,J=9.0Hz,2H),4.45(s,2H),3.96(dd,J1=7.5Hz,J2=6.0Hz,1H).

[0509] Using the above SPPS procedure, the following DOTA conjugates were prepared (see Examples 33-35).

[0510] Example 33: DOTA-Lys(Pte)-OH (Compound 46): [ka] LCMS(ESI):[M+H] + =C 36 H 51 N 12 O 11 Calculated value: 827.37; measured value: 827.30 Selected Data 1 H NMR (500MHz, DMSO-d6, D2O): δ 8.60(s,1H),7.52(d,J=9.0Hz,2H),6.62(d,J=9.0Hz,2H),4.47(s,2H),3.99(dd,J1=9.0Hz,J2=4.0,5.0Hz,1H).

[0511] Example 34: DOTA-Gly-Pro-Pro-Gly-Ser-Ala-Phe-Lys(Pte)-OH (Compound 47): [ka] LCMS(ESI):[M+H] + =C 65 H 90 N 19 O 19 Calculated value: 1440.66; measured value: 1440.73 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.61(s,1H),7.56(d,J=8.5Hz,2H),7.24-7.10(m,5H),6.61(d,J=8.0Hz,2H),4.47(s,2H),4.52-4.40(m,2H),4.40-4.18(m,4H).

[0512] Example 35: DOTA-Gly-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys(Pte)-OH (Compound 48): [ka] LCMS(ESI):[M+H] + =C 74 H 99 N 20 O 20 Calculated value: 1587.73; measured value: 1587.64 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.60(s,1H),7.56(d,J=9.0Hz,2H),7.24-7.08(m,10H),6.59(d,J=9.0Hz,2H),4.45(s,2H),4 .52-4.42(m,2H),4.42-4.36(m,1H),4.32-4.26(m,1H),4.23-4.18(m,1H),4.09-4.00(m,1H).

[0513] DOTA conjugates based on N-α-pteroyl-2,3-diaminopropionic acid: Example 36: Pte-Dap(DOTA-Gly-Tyr(O-carbonylmethyl)-OH)-OH (Compound 49): [ka] Compound 49 was synthesized by solid phase in six steps starting from Fmoc-Dap(N-4-methoxytrityl)-Wang-resin (Table 10).

[0514] [Table 11]

[0515] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step (in addition to Mtt deprotection using 25% HFIP in CHCl). For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 10 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 10 minutes before venting (2×). The resin was washed with DMF (approximately 20 mL × 3), followed by IPA (approximately 20 mL × 3), and then washed again with DMF (approximately 20 mL × 3).

[0516] Procedure B: Mtt cleavage Approximately 20 mL of 25% HFIP in CHCl was added, and argon was bubbled through the solution for 10 minutes. Small amounts of CHCl were added to the reaction vessel to maintain the same volume even with vigorous bubbling. The yellow solution was then drained and repeated five times. The resin was washed with fresh CHCl until the filtrate remained clear. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then again with DMF (approximately 20 mL x 3).

[0517] Step C: Amino acid coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 2 hours and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0518] Step D: Resin cutting The resin was washed with MeOH (approximately 20 mL × 3) and dried under a stream of argon. 25 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% Triisopropylsaline) was added to the peptide synthesis vessel, bubbled with argon for 1 h, emptied, and repeated with cleavage reagent (10 mL × 2 for 5 min). The reaction mixture was concentrated under reduced pressure until 10 mL remained. The product was triturated in 25 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 25 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum.

[0519] Step E: N in pteroic acid 10 -TFA group deprotection and purification The crude precipitate was suspended in water. 20% Na2CO3 was added until the pH of the solution reached 9.5. The clear solution was stirred for 1 h, and LCMS analysis confirmed the formation of the product. The pH of the solution was adjusted to 6.5 using 1N HCl and loaded onto a C18 column. The desired product was purified by reverse-phase chromatography (5-50% acetonitrile in 50 mM ammonium bicarbonate buffer at pH 7.0). The acetonitrile was evaporated under reduced pressure, and the remaining aqueous buffer solution was frozen and removed by lyophilization. [ka] LCMS(ESI):[M+H] + =C 46 H 59 N 14 O 16 Calculated value: 1063.42; measured value: 1063.30 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.63(s,1H),7.55(d,J=9.0Hz,2H),7.06(d,J=9.0Hz,2H),6.77(d,J=9.0Hz,2H),6.62(d,J=8.5Hz,2 H),4.48(s,2H),4.38(s,2H),4.34(dd,J1=7.5Hz,J2=5.0Hz,1H),4.24(dd,J1=7.0Hz,J2=6.5Hz,1H).

[0520] Using the above SPPS procedure, the following DOTA conjugates were prepared (see Example 37).

[0521] Example 37: Pte-Dap(Val-Gly-DOTA)-OH (Compound 50): [ka] LCMS(ESI):[M+H] + =C 38 H 53 N 14 O 13 Calculated value: 913.38; measured value: 913.30 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.66(s,1H),7.61(d,J=9.0Hz,2H),6.66(d,J=8.0Hz,2H),4.50(s,2H),4.46(m,1H),4.26(ABq,J1=13.75Hz,J2=6.5Hz,1H).

[0522] Pteroyl-aspartic acid-based DOTA conjugates: Example 38: Synthesis of Pte-Asp(DOTA-Gly-ε-Lys-OH)-OH (Compound 51): [ka] Compound 51 was synthesized by solid phase in six steps starting from Fmoc-Lys(N-4-methoxytrityl)-Wang-resin (Table 11).

[0523] [Table 12]

[0524] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step (in addition to Mtt deprotection using 25% HFIP in CHCl). For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 10 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 10 minutes before venting (2×). The resin was washed with DMF (approximately 20 mL × 3), followed by IPA (approximately 20 mL × 3), and then washed again with DMF (approximately 20 mL × 3).

[0525] Procedure B: Mtt cleavage Approximately 20 mL of 25% HFIP in CHCl was added, and argon was bubbled through the solution for 10 minutes. Small amounts of CHCl were added to the reaction vessel to maintain the same volume even with vigorous bubbling. The yellow solution was then drained and repeated five times. The resin was washed with fresh CHCl until the filtrate remained clear. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then again with DMF (approximately 20 mL x 3).

[0526] Step C: Amino acid coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 2 hours and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0527] Step D2: Cutting the resin The resin was washed with MeOH (approximately 20 mL × 3) and dried under a stream of argon. 25 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% Triisopropylsaline) was added to the peptide synthesis vessel, bubbled with argon for 1 hour, emptied, and repeated with cleavage reagent (10 mL × 2 for 5 minutes). The filtrate was stirred under argon at 35 °C for 2 hours. The reaction mixture was concentrated under reduced pressure until 10 mL remained. The product was triturated in 25 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 25 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum.

[0528] Step E: N in pteroic acid 10 -TFA group deprotection and purification The crude precipitate was suspended in water. 20% Na2CO3 was added until the pH of the solution reached 9.5. The clear solution was stirred for 1 h, and LCMS analysis confirmed the formation of the product. The pH of the solution was adjusted to 6.5 using 1N HCl and loaded onto a C18 column. The desired product was purified by reverse-phase chromatography (5-50% acetonitrile in 50 mM ammonium bicarbonate buffer at pH 7.0). The acetonitrile was evaporated under reduced pressure, and the remaining aqueous buffer solution was frozen and removed by lyophilization. [ka] LCMS(ESI):[M+H] + =C 42 H 59 N 14 O 15 Calculated value: 999.42; Measured value: 999.46 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.61(s,1H),7.55(d,J=8.0Hz,2H),6.62(d,J=8.5Hz,2H),4.64(dd,J1=7.5Hz,J2=5.5Hz,1H),4.47(s,2H),4.12(dd,J1=8.5Hz,J2=5.5Hz,1H).

[0529] Using the above SPPS procedure, the following DOTA conjugates were prepared (see Example 39).

[0530] Example 39: Pte-Asp(DOTA-Ala-ε-Lys-OH)-OH (compound 52): [ka] LCMS(ESI):[M+H] + =C 43 H 61 N 14 O 15 Calculated value: 1013.44; measured value: 1013.40 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.62(s,1H),7.55(d,J=8.5Hz,2H),6.63(d,J=9.5Hz,2H),4.52-4.42(m,1H),4.48(s,2H),4.12(ABq,J1=14.5Hz,J2=7.0,7.5Hz,1H).

[0531] Pteroyl-aspartic acid-based DOTA conjugates bearing a hippuryllysine motif Example 40: Synthesis of Pte-Asp(DOTA-3-amino-benzoyl-Gly-ε-Lys-OH)-OH (Compound 53): [ka] LCMS(ESI):[M+H] + =C 49 H 64 N 15 O 16 Calculated value: 1118.46; measured value: 1118.50 Selected Data 1H NMR(500MHz,DMSO-d6,D2O):δ 8.60(s,1H),8.26(s,1H),7.90(d,J=7.5Hz,1H),7.55(d,J=9.0Hz,2H),7.44(d,J=7.0Hz,1H),7.26(dd,J1=7.5Hz,J2=8. 0Hz,1H),6.63(d,J=9.0Hz,2H),4.49(dd,J1=8.0Hz,J2=5.5,6.0Hz,1H),4.46(s,2H),4.02(dd,J1=5.0Hz,J2=5.5Hz,1H).

[0532] Pteroyl-aspartic acid-based DOTA conjugates with MVK-motif Example 41: Synthesis of Pte-Asp(DOTA-Met-Val-ε-Lys-OH)-OH (Compound 54): [ka] LCMS(ESI):[M+H] + =C 50 H 74 N 15 O 16 Calculated value for S: 1172.51; measured value: 1172.30 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.61(s,1H),7.54(d,J=8.5Hz,2H),6.62(d,J=8.5Hz,2H),4.51-4.41(m,1H),4.46(s,2H),4.28(m,1H),4.05(d,J=7.0Hz,1H),4.0(m,1H).

[0533] Folate-based DOTA conjugates with MVK-motif Example 42: Synthesis of Boc-Met-Val-Lys-OH (Compound 55): [ka] Compound 55 was synthesized by solid phase in four steps starting from Fmoc-Lys(N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidine)ethyl))chlorotrityl)-resin (Table 12).

[0534] [Table 13]

[0535] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step. For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 10 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 10 minutes before venting (2x). The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0536] Step B2: Dde deprotection For Dde deprotection, a solution of 2% hydrazine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 20 minutes, followed by venting. 2% hydrazine in DMF (approximately 20 mL) was added, and bubbling continued for 20 minutes, followed by venting (2x). The resin was washed with DMF (approximately 20 mL x 3) followed by IPA (approximately 20 mL x 3) and dried.

[0537] Step C: Amino acid coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 2 hours and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0538] Step D3: Cutting the resin The resin was cleaved using 25% HFIP (approximately 20 mL) and 2.5% TIPS in CHCl. ​​Argon was bubbled through the solution for 1 hour and vented into a clean flask. The resin was washed with the cleavage solution for 10 minutes (2x) and vented. The combined cleavage solutions were concentrated to a smaller volume and precipitated with ether. The solid was washed with ether (3x) and dried under high vacuum. [ka] LCMS(ESI):[M+H] + =C 21 H 41 Calculated value for N4O6S: 477.27; Measured value: 477.09 Selected Data 1 H NMR(500MHz,CD3OD):δ 4.24(dd,J1=7.0Hz,J2=5.0Hz,1H),4.20(dd,J1=9.0Hz,J2=5.5Hz,1H),4.18(d,J= 7.5Hz,1H),2.92(t,J1=7.5Hz,J2=7.0Hz,2H),2.46-2.62(m,2H),2.10(s,3H),1.98 -2.07(m,2H),1.81 -1.92(m,2H),1.60 -1.76(m,3H),1.46(s,9H),1.36 -1.46(m,2H),0.98(d,J=7.0Hz,3H),0.97(d,J=6.0Hz,3H).

[0539] Example 43: Synthesis of Boc-Met-Val-Lys(maleimide)-OH (Compound 56): [ka] To a solution of compound 55 (0.0086 g, 0.018 mM) in water (0.3 mL) was added saturated NaHCO (0.13 mL). The reaction was cooled to 0 °C, and N-methoxycarbonyl-maleimide (commercially available, 0.004 g, 0.026 mM) was added. The reaction was stirred for 2 h, and LCMS analysis (20 mM NHHCO, pH 7.4) indicated the reaction was complete. The reaction mixture was treated with 5% citric acid at 0 °C until the pH reached 3.0, extracted with dichloromethane (3 ×), dried over NaSO, concentrated, and dried. The crude compound 56 was confirmed by LCMS and used for the next reaction without further purification. LCMS(ESI):[M+Na] + =C 25 H 40 Calculated value for N4O8SNa: 579.26; Measured value: 579.29

[0540] Example 44: Synthesis of Met-Val-Lys(maleimide)-OH (Compound 57): [ka] To a solution of compound 56 (0.007 g, 0.013 mM) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL) and triisopropylsilane (0.025 mL). The reaction was stirred at room temperature for 30 minutes, and LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the reaction was complete. The reaction mixture was concentrated, coevaporated with dichloromethane (3x), and dried under high vacuum. Crude compound 57 was confirmed by LCMS and used for the next reaction without further purification. LCMS(ESI):[M+H] + =C 20 H 33 Calculated value for N4O6S: 457.20; Measured value: 457.17

[0541] Example 45: Synthesis of DOTA-Bn-NHC(S)NH-Met-Val-Lys(Mal-S-Cys-Asp-Asp-Arg-Asp-folate)-OH (Compound 58): [ka] To a solution of compound 57 (0.007 g, 0.013 mM) in DMF (0.5 mL) was added DOTA-benzyl iso-thiocyanate (commercially obtained, 0.035 g, 0.063 mM) and triethylamine (0.017 mL, 0.13 mM). The resulting homogeneous solution was stirred under argon at ambient temperature for 2 hours. LCMS analysis confirmed the formation of the product (compound 59). Compound 60 (0.014 g, 0.014 mM) synthesized according to Vlahov et al., Bioorg. & Med. Chem. Letters 16 (2006), 5093-5096, in DMSO (0.5 mL) and triethylamine (0.017 mL, 0.13 mM) were added and stirred under argon at ambient temperature for 1 hour. LCMS analysis confirmed the formation of the product. The reaction mixture was diluted with DMSO and directly loaded onto preparative HPLC (mobile phase A = 50 mM ammonium bicarbonate, pH = 7.0. B = ACN. Method: 5 to 50% B in 25 min) for purification. Fractions containing the desired product were collected, combined, removed from the ACN, and lyophilized to give conjugate compound 58 as a yellow solid. LCMS(ESI):[M+2H] 2+ =C 84 H 117 N 24 O 31 Calculated value for S3: 1027.37; measured value: 1027.50 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.63(s,1H),7.60(d,J=8.5Hz,2H),7.62-7.35(m,2H),7.35-7.00(m,2H),6.63(d,J=8.5Hz ,2H),5.00-4.84(m,1H),4.67-4.54(m,1H),4.54-4.44(m,3H),4.44-4.36(m,1H),4.26(br s,1H),4.19(br s,1H),4.17-3.99(m,4H).

[0542] Example 46: Pte-Tyr(OCH 2 Synthesis of CO-EDA-DOTA)-OH (Compound 61): [ka] To a solution of compound 36 (0.043 g, 0.083 mM) in DCM (4.0 mL), EDA-DOTA (O t Bu)3 (commercially obtained, 0.058 g, 0.083 mM), PyBop (0.048 g, 0.091 mM), and diisopropylethylamine (0.145 mL, 0.83 mM) were added. The resulting homogeneous solution was stirred at ambient temperature under argon for 2 h. LCMS analysis confirmed the formation of the coupled product. Diethylamine (1.4 mL) was added and stirred at ambient temperature under argon for 3 h. LCMS analysis confirmed the formation of the de-Fmoc product. DCM and diethylamine were evaporated, and the residue was co-evaporated with DCM (3x) and dried. The residue was dissolved in DMSO (1.0 mL) and N 10 -TFA-pteroic acid (0.034 g, 0.083 mM), PyBop (0.048 g, 0.091 mM), and diisopropylethylamine (0.145 mL, 0.83 mM) were added. The resulting homogeneous solution was stirred under argon at ambient temperature for 2 h. LCMS analysis confirmed the coupling reaction was complete. The reaction mixture was precipitated with ether. The solid was washed with ether (3×) and dried under high vacuum to give crude protected 61. The crude material was treated with 95% TFA, 2.5% HO, 2.5% Triisopropylsaline (25 mL) and stirred under argon at 35° C. for 2 h. LCMS analysis indicated the product, N 10 The formation of -TFA-61 was confirmed. The reaction mixture was concentrated under reduced pressure until 5 ml remained. The product was triturated in 25 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 25 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum. The crude precipitate was suspended in water. 20% Na2CO3 was added until the pH of the solution reached 9.5. The clear solution was stirred for 1 hour, and LCMS analysis showed that N 10The deprotection of -TFA was confirmed. The pH of the solution was adjusted to 6.5 using 1N HCl and loaded onto a C18 column. The desired product was purified by reverse-phase chromatography (5-50% acetonitrile in 50 mM ammonium bicarbonate buffer at pH 7.0). The acetonitrile was evaporated under reduced pressure, and the remaining aqueous buffer solution was frozen and removed by lyophilization to give compound 61. LCMS(ESI):[M+H] + =C 43 H 56 N 13 O 13 Calculated value: 962.40; Measured value: 962.50 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.61(s,1H),7.48(d,J=9.0Hz,2H),7.08(d,J=8.5Hz,2H),6.77(d,J=9.0Hz,2H),6 .58(d,J=9.0Hz,2H),4.45(s,2H),4.41(s,2H),4.36(dd,J1=9.0Hz,J2=5.0Hz,1H).

[0543] Example 47: Cbz-Tyr(O—CH 2 CH 2 NHBoc)-O t Synthesis of Bu (compound 62): [ka] Cbz-Tyr-O in dry acetone (10 mL) t To a solution of Bu (commercially obtained, 1.11 g, 3.0 mM) was added potassium carbonate (1.24 g, 9.0 mM) and stirred for 5 minutes. Boc-aminoethyl bromide (commercially obtained, 0.74 g, 3.3 mM) was added. The reaction was refluxed for 24 hours, and LCMS analysis (20 mM NH4HCO3, pH 7.4) indicated the formation of the product. The reaction mixture was cooled to ambient temperature, filtered, and concentrated. The residue was dissolved in dichloromethane and purified by combi-flash chromatography (0-100% ethyl acetate in petroleum ether) to give compound 62. LCMS(ESI):[M+Na] + =C 28 H 38 Calculated value for N2O7Na: 537.27; Found: 537.40 1 H NMR(500MHz,CDCl3):δδ 7.29 - 7.39(m,5H),7.06(d,J=9.0Hz,2H),6.79(d,J=8.5Hz,2H),5.22(d,J=8.5Hz,1H),5.10(ABq,J1=19.5Hz,J2=12.5Hz,2H),5.0(br s,1H),4.50(dd,J1=13.75Hz,J2=6.0Hz,5.5Hz,1H),3.99(t,J1=5.5Hz,J2=5. 0Hz,2H),3.53(d,J=5.0Hz,2H),2.96-3.09(m,2H),1.46(s,9H),1.42(s,9H).

[0544] Example 48: Tyr(O-CH 2 CH 2 NHBoc)-O t Synthesis of Bu (compound 63): [ka] To a solution of compound 62 (0.38 g, 0.74 mM) in ethyl acetate (12 mL), 10% Pd / C (0.13 g) was added and stirred under a H atmosphere (balloon) for 3 hours. LCMS analysis (20 mM NH4HCO3, pH 7.4) showed the reaction was complete. The reaction mixture was filtered, concentrated, and dried to give compound 63. The crude material was used directly for the next coupling reaction. LCMS(ESI):[M+H] + =C 20 H 33 Calculated for N2O5: 381.23; Measured: 381.49

[0545] Example 49: Pte-Tyr(OCH 2 CH 2 Synthesis of -NH-DOTA)-OH (Compound 64): [ka] To a solution of compound 63 (0.075 g, 0.197 mM) in DCM (1.0 mL) was added N 10 -TFA-pteroic acid (0.089 g, 0.217 mM) was added. PyBop (0.113 g, 0.217 mM) and diisopropylethylamine (0.189 mL, 1.09 mM) were added. The resulting homogeneous solution was stirred under argon at ambient temperature for 2 hours. LCMS analysis confirmed the coupling reaction was complete. DCM was removed under reduced pressure, diluted with water, and lyophilized for 16 hours. The crude material was treated with 95% TFA, 2.5% HO, 2.5% triisopropylsaline (25 mL) and stirred at room temperature under argon for 1 hour. LCMS analysis confirmed product formation. The reaction mixture was concentrated under reduced pressure until 5 mL remained. The product was triturated in 25 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 25 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum for 18 hours to give compound 65. The crude product was used directly for the next coupling reaction. LCMS(ESI):[M+H] + =C 27 H 26 Calculated for F3N8O6: 615.18; Found: 614.88

[0546] To a solution of compound 65 (0.055 g, 0.090 mM) in DMSO (1.5 mL) was added DOTA-ONHS (commercially obtained, 0.068 g, 0.090 mM). Diisopropylethylamine (0.156 mL, 0.895 mM) was added. The resulting homogeneous solution was stirred under argon at ambient temperature for 1 hour. LCMS analysis confirmed the coupling reaction was complete. An oil was separated by trituration in 10 mL of diethyl ether. It was centrifuged and washed with ether (3 × 10 mL). The gummy product was dried under a stream of argon followed by high vacuum for 18 hours. The crude material was suspended in water. 20% Na2CO3 was added until the pH of the solution reached 9.5. The clear solution was stirred for 1 hour, and LCMS analysis showed that N 10 The deprotection of -TFA was confirmed. The pH of the solution was adjusted to 6.5 using 1N HCl and loaded onto a C18 column. The desired product was purified by reverse-phase chromatography (5-50% acetonitrile in 50 mM ammonium bicarbonate buffer at pH 7.0). The acetonitrile was evaporated under reduced pressure, and the remaining aqueous buffer was frozen and removed by lyophilization to give compound 64. LCMS(ESI):[M+H] + =C 41 H 53 N 12 O 12 Calculated value: 905.38; measured value: 905.50 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 8.60(s,1H),7.43(d,J=9.0Hz,2H),7.04(d,J=8.5Hz,2H),6.71(d,J=8.5Hz, 2H),6.57(d,J=8.5Hz,2H),4.45(s,2H),4.34(dd,J1=8.5Hz,J2=5.0Hz,1H).

[0547] Benzoyl-aspartic acid based DOTA conjugates: Example 50: Synthesis of Benzoyl-Asp(DOTA-Gly-ε-Lys-OH)-OH (Compound 66): [ka] Compound 66 was synthesized by solid phase in six steps starting from Fmoc-Lys(N-4-methoxytrityl)-Wang-resin (Table 13).

[0548] [Table 14]

[0549] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step (in addition to Mtt deprotection using 25% HFIP in CHCl). For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 10 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 10 minutes before venting (2×). The resin was washed with DMF (approximately 20 mL × 3), followed by IPA (approximately 20 mL × 3), and then washed again with DMF (approximately 20 mL × 3).

[0550] Procedure B: Mtt cleavage Approximately 20 mL of 25% HFIP in CHCl was added, and argon was bubbled through the solution for 10 minutes. Small amounts of CHCl were added to the reaction vessel to maintain the same volume even with vigorous bubbling. The yellow solution was then drained and repeated five times. The resin was washed with fresh CHCl until the filtrate remained clear. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then again with DMF (approximately 20 mL x 3).

[0551] Step C: Amino acid coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was bubbled through the solution for 2 hours and then vented. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then washed again with DMF (approximately 20 mL x 3).

[0552] Step D2: Cutting the resin The resin was washed with MeOH (approximately 20 mL × 3) and dried under a stream of argon. 25 mL of cleavage reagent (95% TFA, 2.5% HO, 2.5% Triisopropylsaline) was added to the peptide synthesis vessel, bubbled with argon for 1 hour, emptied, and repeated with cleavage reagent (10 mL × 2 for 5 minutes). The filtrate was stirred under argon at 35 °C for 2 hours. The reaction mixture was concentrated under reduced pressure until 10 mL remained. The product was triturated in 25 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The previous step was repeated twice by resuspending the pellet in 25 mL of diethyl ether and centrifuging. The pellet was dried under a stream of argon followed by high vacuum. [ka] LCMS(ESI):[M+H] + =C 35 H 53 N8O 14 Calculated value: 809.36; measured value: 809.40 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 7.79(d,J=8.5Hz,2H),7.54(dt,J1=7.50Hz,J2=1.5Hz,1H),7.47(dt,J1=7.50Hz,J2=1 .0Hz,2H),4.74(dt,J1=7.00Hz,J2=1.5Hz,1H),4.13(dd,J1=7.250Hz,J2=5.0Hz,1H).

[0553] The compound of Example 51 was synthesized using similar procedures as described in the examples above using the appropriate starting materials.

[0554] Example 51: Synthesis of 4-((naphthalen-2-ylmethyl)amino)benzoyl-Lys(DOTA)-OH (Compound 67): [ka] LCMS(ESI):[M+H] + =C 40H 54 N7O 10 Calculated value: 792.39; measured value: 792.18 Selected Data 1 H NMR(500MHz,DMSO-d6,D2O):δ 7.85(d,J=8.5Hz,2H),7.83-7.77(m,2H),7.58(d,J=8.5Hz,2H),7.51-7.41(m,3H),6.61(d,J=8.5Hz,2H),4.47(s,2H),4.20(m,1H).

[0555] Example 52: Synthesis of Pte-Dap(Gly-DOTA)-OH (Compound 68): [ka] Compound 68 was synthesized by solid phase in five steps starting from Fmoc-Dap(N-4-methoxytrityl)-Wang-resin.

[0556] [Table 15]

[0557] Step A: Fmoc deprotection A deprotection step was performed before each amino acid coupling step (in addition to Mtt deprotection using 25% HFIP in CHCl). For Fmoc deprotection, a solution of 20% piperidine in DMF (approximately 20 mL) was added. Argon was bubbled through the solution for 10 minutes, followed by venting. 20% piperidine in DMF (approximately 20 mL) was added, and bubbling continued for 10 minutes before venting (2×). The resin was washed with DMF (approximately 20 mL × 3), followed by IPA (approximately 20 mL × 3), and then washed again with DMF (approximately 20 mL × 3).

[0558] Procedure B: Mtt cleavage Approximately 20 mL of 25% HFIP in CHCl was added, and argon was bubbled through the solution for 10 minutes. Small amounts of CHCl were added to the reaction vessel to maintain the same volume even with vigorous bubbling. The yellow solution was then drained and repeated five times. The resin was washed with fresh CHCl until the filtrate remained clear. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3), and then again with DMF (approximately 20 mL x 3).

[0559] Step C: Amino acid coupling Amino acid solution in DMF (approximately 20 mL), i Pr2NEt and PyBOP were added to a peptide synthesis vessel. Argon was...

Claims

1. Compounds of formula (I) BL-(L ｘ ) ｋ -A (I) or a pharma- ceutically acceptable salt thereof (In the formula, BL is folate receptor binding ligand; A is a metal, a radioactive element, Si- １８ F, B- １８ F or Al- １８ A is a chelating group Ch which may contain F, or A is a radiolabeled prosthetic group PG, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each L Ｘ are independently AA, L １ , L ２ Or L ３ and Each AA is independently an amino acid residue; Each L １ are independently expressed as 【Chemistry 1】 (In the formula, R １６ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, —C(O)R １９ , -C(O)OR １９ and -C(O)NR １９ R １９’ C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl and C ２ ~C ６ Each hydrogen atom in an alkynyl is a halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, and C ２ ~C ６ Alkynyl, -OR ２０ , -OC(O)R ２０ , -OC(O)NR ２０ R ２０’ , -OS(O)R ２０ , -OS(O) ２ R ２０ , -SR ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -S(O)NR ２０ R ２０’ , -S(O) ２ N.R. ２０ R ２０’ , -OS(O)NR ２０ R ２０’ , -OS(O) ２ N.R. ２０ R ２０’ , -NR ２０ R ２０’ , -NR ２０ C(O)R ２１ , -NR ２０ C(O)OR ２１ , -NR ２０ C(O)NR ２１ R ２１’ , -NR ２０ S(O)R ２１ , -NR ２０ S (O) ２ R ２１ , -NR ２０ S(O)NR ２１ R ２１’ , -NR ２０ S (O) ２ N.R. ２１ R ２１’ , -C(O)R ２０ , -C(O)OR ２０ or -C(O)NR ２０ R ２０’ independently and optionally substituted by; Each R １７ and R １７’ are independently H, halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ２２ , -OC(O)R ２２ , -OC(O)NR ２２ R ２２’ , -OS(O)R ２２ , -OS(O) ２ R ２２ , -SR ２２ , -S(O)R ２２ , -S(O) ２ R ２２ , -S(O)NR ２２ R ２２’ , -S(O) ２ N.R. ２２ R ２２’ , -OS(O)NR ２２ R ２２’ , -OS(O) ２ N.R. ２２ R ２２’ , -NR ２２ R ２２’ , -NR ２２ C(O)R ２３ , -NR ２２ C(O)OR ２３ , -NR ２２ C(O)NR ２３ R ２３’ , -NR ２２ S(O)R ２３ , -NR ２２ S (O) ２ R ２３ , -NR ２２ S(O)NR ２３ R ２３’ , -NR ２２ S (O) ２ N.R. ２３ R ２３’ , -C(O)R ２２ , -C(O)OR ２２ and -C(O)NR ２２ R ２２’ C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Each hydrogen atom in the aryl and 5- to 7-membered heteroaryl is selected from halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, -OR ２４ , -OC(O)R ２４ , -OC(O)NR ２４ R ２４’ , -OS(O)R ２４ , -OS(O) ２ R ２４ , -SR ２４ , -S(O)R ２４ , -S(O) ２ R ２４ , -S(O)NR ２４ R ２４’ , -S(O) ２ N.R. ２４ R ２４’ , -OS(O)NR ２４ R ２４’ , -OS(O) ２ N.R. ２４ R ２４’ , -NR ２４ R ２４’ , -NR ２４ C(O)R ２５ , -NR ２４ C(O)OR ２５ , -NR ２４ C(O)NR ２５ R ２５’ , -NR ２４ S(O)R ２５ , -NR ２４ S (O) ２ R ２５ , -NR ２４ S(O)NR ２５ R ２５’ , -NR ２４ S (O) ２ N.R. ２５ R ２５’ , -C(O)R ２４ , -C(O)OR ２４ or -C(O)NR ２４ R ２４’ or R １７ and R １７’ Combine them and you get C ４ ~C ６ may form a cycloalkyl or a 4- to 6-membered heterocycle, C ４ ~C ６ Each hydrogen atom in the cycloalkyl or 4- to 6-membered heterocycle is selected from halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ２４ , -OC(O)R ２４ , -OC(O)NR ２４ R ２４’ , -OS(O)R ２４ , -OS(O) ２ R ２４ , -SR ２４ , -S(O)R ２４ , -S(O) ２ R ２４ , -S(O)NR ２４ R ２４’ , -S(O) ２ N.R. ２４ R ２４’ , -OS(O)NR ２４ R ２４’ , -OS(O) ２ N.R. ２４ R ２４’ , -NR ２４ R ２４’ , -NR ２４ C(O)R ２５ , -NR ２４ C(O)OR ２５ , -NR ２４ C(O)NR ２５ R ２５’ , -NR ２４ S(O)R ２５ , -NR ２４ S (O) ２ R ２５ , -NR ２４ S(O)NR ２５ R ２５’ , -NR ２４ S (O) ２ N.R. ２５ R ２５’ , -C(O)R ２４ , -C(O)OR ２４ or -C(O)NR ２４ R ２４’ independently and optionally substituted by; R １８ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ２６ , -OC(O)R ２６ , -OC(O)NR ２６ R ２６’ , -OS(O)R ２６ , -OS(O) ２ R ２６ , -SR ２６ , -S(O)R ２６ , -S(O) ２ R ２６ , -S(O)NR ２６ R ２６’ , -S(O) ２ N.R. ２６ R ２６’ , -OS(O)NR ２６ R ２６’ , -OS(O) ２ N.R. ２６ R ２６’ , -NR ２６ R ２６’ , -NR ２６ C(O)R ２７ , -NR ２６ C(O)OR ２７ , -NR ２６ C(O)NR ２７ R ２７’ , -NR ２６ C (=NR ２６’’ ) N.R. ２７ R ２７’ , -NR ２６ S(O)R ２７ , -NR ２６ S (O) ２ R ２７ , -NR ２６ S(O)NR ２７ R ２７’ , -NR ２６ S (O) ２ N.R. ２７ R ２７’ , -C(O)R ２６ , -C(O)OR ２６ and -C(O)NR ２６ R ２６’ C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Each hydrogen atom in the aryl and 5- to 7-membered heteroaryl is selected from halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, -(CH ２ ) ｐ OR ２８ , -(CH ２ ) ｐ (O.C.H. ２ ) ｑ OR ２８ , -(CH ２ ) ｐ (O.C.H. ２ CH ２ ) ｑ OR ２８ , -OR ２９ , -OC(O)R ２９ , -OC(O)NR ２９ R ２９’ , -OS(O)R ２９ , -OS(O) ２ R ２９ , -(CH ２ ) ｐ OS (O) ２ OR ２９ , -OS(O) ２ OR ２９ , -SR ２９ , -S(O)R ２９ , -S(O) ２ R ２９ , -S(O)NR ２９ R ２９’ , -S(O) ２ N.R. ２９ R ２９’ , -OS(O)NR ２９ R ２９’ , -OS(O) ２ N.R. ２９ R ２９’ , -NR ２９ R ２９’ , -NR ２９ C(O)R ３０ , -NR ２９ C(O)OR ３０ , -NR ２９ C(O)NR ３０ R ３０’ , -NR ２９ S(O)R ３０ , -NR ２９ S (O) ２ R ３０ , -NR ２９ S(O)NR ３０ R ３０’ , -NR ２９ S (O) ２ N.R. ３０ R ３０’ , -C(O)R ２９ , -C(O)OR ２９ or -C(O)NR ２９ R ２９’ independently and optionally substituted by; Each R １９ , R １９’ , R ２０ , R ２０’ , R ２１ , R ２１’ , R ２２ , R ２２’ , R ２３ , R ２３’ , R ２４ , R ２４’ , R ２５ , R ２５’ , R ２６ , R ２６’ , R ２６’’ , R ２９ , R ２９’ , R ３０ and R ３０’ are independently H, C １ ~C ７ Alkyl, C ２ ~C ７ Alkenyl, C ２ ~C ７ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ aryl and 5- to 7-membered heteroaryl; １ ~C ７ Alkyl, C ２ ~C ７ Alkenyl, C ２ ~C ７ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Each hydrogen atom in the aryl or 5- to 7-membered heteroaryl is preferably a halogen, —OH, —SH, —NH ２ Or -CO ２ independently optionally substituted by H; R ２７ and R ２７’ are each independently H, C １ ~C ９ Alkyl, C ２ ~C ９ Alkenyl, C ２ ~C ９ Alkynyl, C ３ ~C ６ Cycloalkyl, -(CH ２ ) ｐ (sugar), -(CH ２ ) ｐ (O.C.H. ２ CH ２ ) ｑ -(sugar) and -(CH ２ ) ｐ (O.C.H. ２ CH ２ CH ２ ) ｑ (sugar); R ２８ is H, C １ ~C ７ Alkyl, C ２ ~C ７ Alkenyl, C ２ ~C ７ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ aryl, 5-7 membered heteroaryl, or sugar; w is 1, 2, 3, 4 or 5; p is 1, 2, 3, 4 or 5; q is 1, 2, 3, 4 or 5; Each L ２ are independently expressed as 【Chemistry 2】 (In the formula, Each R ３１ and R ３１’ are independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ cycloalkyl; １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ Each hydrogen atom in a cycloalkyl can be replaced by a halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ３２ , -OC(O)R ３２ , -OC(O)NR ３２ R ３２’ , -OS(O)R ３２ , -OS(O) ２ R ３２ , -SR ３２ , -S(O)R ３２ , -S(O) ２ R ３２ , -S(O)NR ３２ R ３２’ , -S(O) ２ N.R. ３２ R ３２’ , -OS(O)NR ３２ R ３２’ , -OS(O) ２ N.R. ３２ R ３２’ , -NR ３２ R ３２’ , -NR ３２ C(O)R ３３ , -NR ３２ C(O)OR ３３ , -NR ３２ C(O)NR ３３ R ３３’ , -NR ３２ S(O)R ３３ , -NR ３２ S (O) ２ R ３３ , -NR ３２ S(O)NR ３３ R ３３’ , -NR ３２ S (O) ２ N.R. ３３ R ３３’ , -C(O)R ３２ , -C(O)OR ３２ or -C(O)NR ３２ R ３２’ independently and optionally substituted by; X ６ is C １ ~C ６ Alkyl or C ６ ~C １０ Aryl (C １ ~C ６ alkyl), and C １ ~C ６ Alkyl and C ６ ~C １０ Aryl (C １ ~C ６ Each hydrogen atom in the alkyl group is a halogen, １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ３４ , -OC(O)R ３４ , -OC(O)NR ３４ R ３４’ , -OS(O)R ３４ , -OS(O) ２ R ３４ , -SR ３４ , -S(O)R ３４ , -S(O) ２ R ３４ , -S(O)NR ３４ R ３４’ , -S(O) ２ N.R. ３４ R ３４’ , -OS(O)NR ３４ R ３４’ , -OS(O) ２ N.R. ３４ R ３４’ , -NR ３４ R ３４’ , -NR ３４ C(O)R ３５ , -NR ３４ C(O)OR ３５ , -NR ３４ C(O)NR ３５ R ３５’ , -NR ３４ S(O)R ３５ , -NR ３４ S (O) ２ R ３５ , -NR ３４ S(O)NR ３５ R ３５’ , -NR ３４ S (O) ２ N.R. ３５ R ３５’ , -C(O)R ３４ , -C(O)OR ３４ or -C(O)NR ３４ R ３４’ independently and optionally substituted by; Each R ３２ , R ３２’ , R ３３ , R ３３’ , R ３４ , R ３４’ , R ３５ and R ３５’ are independently H, C １ ~C ７ Alkyl, C ２ ~C ７ Alkenyl, C ２ ~C ７ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ aryl, and 5- to 7-membered heteroaryl; R ３６ are independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ cycloalkyl; １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ Each hydrogen atom in a cycloalkyl can be replaced by a halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ３７ , -OC(O)R ３７ , -OC(O)NR ３７ R ３７’ , -OS(O)R ３７ , -OS(O) ２ R ３７ , -SR ３７ , -S(O)R ３７ , -S(O) ２ R ３７ , -S(O)NR ３７ R ３７’ , -S(O) ２ N.R. ３７ R ３７’ , -OS(O)NR ３７ R ３７’ , -OS(O) ２ N.R. ３７ R ３７’ , -NR ３７ R ３７’ , -NR ３７ C(O)R ３８ , -NR ３７ C(O)OR ３８ , -NR ３７ C(O)NR ３８ R ３８’ , -NR ３７ S(O)R ３８ , -NR ３７ S (O) ２ R ３８ , -NR ３７ S(O)NR ３８ R ３８’ , -NR ３７ S (O) ２ N.R. ３８ R ３８’ , -C(O)R ３７ , -C(O)OR ３７ or -C(O)NR ３７ R ３７’ R ３７ , R ３７’ , R ３８ and R ３８’ are each independently H, C １ ~C ７ Alkyl, C ２ ~C ７ Alkenyl, C ２ ~C ７ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ aryl and 5-7 membered heteroaryl; Each L ３ is independently １ ~C ６ Alkylene, -OC １ ~C ６ Alkylene, -SC １ ~C ６ Alkylene, C ３ ~C ６ Cycloalkylene, -C(O)C ３ ~C ６ Cycloalkylene-, -C(O)C ３ ~C ６ Cycloalkylene-(CR ３９ R ３９’ ) ｒ -, -C(O)C ３ ~C ６ Cycloalkylene-(CR ３９ R ３９’ ) ｒ N.R. ３７ -, 3- to 7-membered heterocycloalkylene, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -NR ３６ (CR ３６’ R ３６’’ ) ｒ -S-(succinimidyl)-, -(CR ３６’ R ３６’’ ) ｒ C(O)NR ３７ -, - (CR ３９ R ３９’ ) ｒ C(O)-,-(CR ３９ R ３９’ ) ｒ OC(O)-,-S(CR ３９ R ３９’ ) ｒ OC(O)-, -C(O)(CR ３９ R ３９’ ) ｒ -, -C(O)O(CR ３９ R ３９’ ) ｒ --, --NR ３７ C(O)(CR ３９ R ３９’ ) ｒ -, - (CR ３９ R ３９’ ) ｒ C(O)NR ３７ -、-NR ３７ C(O)(CR ３９’ R ３９’’ ) ｒ S-、-NR ３７ (CR ３９ R ３９’ ) ｒ -、-(CR ３９ R ３９’ ) ｒ NR ３８ -、-NR ３７ (CR ３９ R ３９’ ) ｒ NR ３８ -、-NR ３７ (CR ３９ R ３９’ ) ｒ S-、-NR ３７ (CR ３９ R ３９’ CR ３９ R ３９’ O) ｒ -、-NR ３７ (CR ３９ R ３９’ CR ３９ R ３９’ O) ｒｐ -(CR ３６ R ３６’ ) ｔ C(O)-、-C(O)(CR ３６ R ３６’ ) ｔ -(OCR ３９ R ３９’ CR ３９ R ３９’ ) ｒｐ -NR ３７ -、-(CR ３９ R ３９’ CR ３９ R ３９’ O) ｒ -(CR ３６ R ３６’ ) ｔ C(O)-、-C(O)(CR ３６ R ３６’ ) ｔ (OCR ３９ R ３９’ CR ３９ R ３９’ CR ３９ R ３９’ ) ｒ -、-C(O)(CR ３６ R ３６’ ) ｔ (OCR ３９ R ３９’ CR ３９ R ３９’ CR ３９ R ３９’ ) ｒ N.R. ３７ -, -C(O)(CR ３６ R ３６’ ) ｒ -O-(C ６ ~C １０ aryl)-(CR ３６’’ R ３６’’’ ) ｔ N.R. ３７ --, --NR ３７ (CR ３６ R ３６’ ) ｒ - (C ６ ~C １０ aryl)-O-(CR ３６’’ R ３６’’’ ) ｔ C(O)-, -C(O)-(CR ３６ R ３６’ ) ｒ -NR ３７ -C(O)-(C ６ ~C １０ Aryl)-NR ３７’ --, --NR ３７ - (C ６ ~C １０ aryl)-C(O)-NR ３７’ - (CR ３６ R ３６’ ) ｒ -C(O)-, -NR ３７ (CR ３６ R ３６’ ) ｒ - (C ６ ~C １０ aryl)-O-(CR ３６’’ R ３６’’’ ) ｔ -, - (CR ３６’’ R ３６’’’ ) ｔ -O-(C ６ ~C １０ aryl)-(CR ３６ R ３６’ ) ｒ -NR ３７ --, --NR ３７ (CR ３６ R ３６’ ) ｒ - (C ６ ~C １０ aryl)-O-(CR ３６’’ R ３６’’’ ) ｔ -NR ３７’ - or -NR ３７’ - (CR ３６’’ R ３６’’’ ) ｔ -O-(C ６ ~C １０ aryl)-(CR ３６ R ３６’ ) ｒ -NR ３７ - and C ６ ~C １０ Each hydrogen atom in an aryl is a halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ３７ , -OC(O)R ３７ , -OC(O)NR ３７ R ３７’ , -OS(O)R ３７ , -OS(O) ２ R ３７ , -SR ３７ , -S(O)R ３７ , -S(O) ２ R ３７ , -S(O)NR ３７ R ３７’ , -S(O) ２ N.R. ３７ R ３７’ , -OS(O)NR ３７ R ３７’ , -OS(O) ２ N.R. ３７ R ３７’ , -NR ３７ R ３７’ , -NR ３７ C(O)R ３８ , -NR ３７ C(O)OR ３８ , -NR ３７ C(O)NR ３８ R ３８’ , -NR ３７ S(O)R ３８ , -NR ３７ S (O) ２ R ３８ , -NR ３７ S(O)NR ３８ R ３８’ , -NR ３７ S (O) ２ N.R. ３８ R ３８’ , -C(O)R ３７ , -C(O)OR ３７ or -C(O)NR ３７ R ３７’ independently and optionally substituted by; During the ceremony, Each R ３６ , R ３６’ , R ３６’’ and R ３６’’’ are independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, —C(O)R ３７ , -C(O)OR ３７ and -C(O)NR ３７ R ３７’ C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl and C ３ ~C ６ Each hydrogen atom in a cycloalkyl can be replaced by a halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ３７ , -OC(O)R ３７ , -OC(O)NR ３７ R ３７’ , -OS(O)R ３７ , -OS(O) ２ R ３７ , -SR ３７ , -S(O)R ３７ , -S(O) ２ R ３７ , -S(O)NR ３７ R ３７’ , -S(O) ２ N.R. ３７ R ３７’ , -OS(O)NR ３７ R ３７’ , -OS(O) ２ N.R. ３７ R ３７’ , -NR ３７ R ３７’ , -NR ３７ C(O)R ３８ , -NR ３７ C(O)OR ３８ , -NR ３７ C(O)NR ３８ R ３８’ , -NR ３７ S(O)R ３８ , -NR ３７ S (O) ２ R ３８ , -NR ３７ S(O)NR ３８ R ３８’ , -NR ３７ S (O) ２ N.R. ３８ R ３８’ , -C(O)R ３７ , -C(O)OR ３７ or -C(O)NR ３７ R ３７’ independently and optionally substituted by; R ３７ , R ３７’ , R ３８ and R ３８’ are each independently H, C １ ~C ７ Alkyl, C ２ ~C ７ Alkenyl, C ２ ~C ７ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ selected from the group consisting of aryl and 5-7 membered heteroaryl; Each R ３９ and R ３９’ are independently H, halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ Aryl, 5- to 7-membered heteroaryl, -OR ４０ , -OC(O)R ４０ , -OC(O)NR ４０ R ４０’ , -OS(O)R ４０ , -OS(O) ２ R ４０ , -SR ４０ , -S(O)R ４０ , -S(O) ２ R ４０ , -S(O)NR ４０ R ４０’ , -S(O) ２ N.R. ４０ R ４０’ , -OS(O)NR ４０ R ４０’ , -OS(O) ２ N.R. ４０ R ４０’ , -NR ４０ R ４０’ , -NR ４０ C(O)R ４１ , -NR ４０ C(O)OR ４１ , -NR ４０ C(O)NR ４１ R ４１’ , -NR ４０ S(O)R ４１ , -NR ４０ S (O) ２ R ４１ , -NR ４０ S(O)NR ４１ R ４１’ , -NR ４０ S (O) ２ N.R. ４１ R ４１’ , -C(O)R ４０ , -C(O)OR ４０ and -C(O)NR ４０ R ４０’ selected from the group consisting of: R ４０ , R ４０’ , R ４１ and R ４１’ are each independently H, C １ ~C ７ Alkyl, C ２ ~C ７ Alkenyl, C ２ ~C ７ Alkynyl, C ３ ~C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ ~C １０ selected from the group consisting of aryl and 5-7 membered heteroaryl; each r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each rp is independently an integer from 1 to 80; each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Each * represents a covalent bond; When k is greater than 3, the L ｘ At least two of the following are independently 【Chemistry 3】 is selected from; and The compound is 【Chemistry 4】 , tautomers of (E1)-(E5), compounds of (E1)-(E5) to which a metal or radioactive element is chelated, or pharmaceutical salts thereof).

2. 2. A compound of claim 1, or a pharma- ceutically acceptable salt thereof, During the ceremony, Each L １ are independently expressed as 【Chemistry 5】 (In the formula, R １６ is H, Each R １７ and R １７’ are independently H, C １ ~C ６ alkyl, or -C(O)OH; R １８ are independently H, C ６ ~C １０ Aryl, -OH -SH, -NHC(=NH ’ ) N.H. ２ or -C(O)OH, ６ ~C １０ each hydrogen atom in the aryl is independently optionally replaced by a halogen; Each L ２ are independently expressed as 【Chemistry 6】 (In the formula, R ３１ and R ３１’ is H, R ３６ is H; and Each L ３ are independently -C(O)C ３ ~C ６ Cycloalkylene-(CH ２ ) ｒ NH-, -(CR ３９ R ３９’ ) ｒ C(O)-, -C(O)(CR ３９ R ３９’ ) ｒ -, -NH(CR ３９ R ３９’ ) ｒ -, - (CR ３９ R ３９’ ) ｒ NH-, -NH(CR ３９ R ３９’ ) ｒ NH-, -NH(CH ２ CH ２ O) ｒｐ - (CR ３６ R ３６’ ) ｔ C(O)-, -C(O)(CR ３６ R ３６’ ) ｔ - (OCR ３９ R ３９’ CR ３９ R ３９’ ) ｒｐ -NH-, -C(O)(CR ３６ R ３６’ ) ｒ -O-(C ６ ~C １０ aryl)-(CR ３６’’ R ３６’’’ ) ｔ NH-, -NH(CR ３６ R ３６’ ) ｒ - (C ６ ~C １０ aryl)-O-(CR ３６’’ R ３６’’’ ) ｔ C(O)-, -C(O)-(CR ３６ R ３６’ ) ｒ -NH-C(O)-(C ６ ~C １０ Aryl)-NH-, -NR ３７ - (C ６ ~C １０ aryl)-C(O)-NH-(CR ３６ R ３６’ ) ｒ -C(O)-, -NH(CR ３６ R ３６’ ) ｒ - (C ６ ~C １０ aryl)-O-(CR ３６’’ R ３６’’’ ) ｔ -, - (CR ３６’’ R ３６’’’ ) ｔ -O-(C ６ ~C １０ aryl)-(CR ３６ R ３６’ ) ｒ -NH-, -NH(CR ３６ R ３６’ ) ｒ - (C ６ ~C １０ aryl)-O-(CR ３６’’ R ３６’’’ ) ｔ -NH- or -NH-(CR ３６’’ R ３６’’’ ) ｔ -O-(C ６ ~C １０ aryl)-(CR ３６ R ３６’ ) ｒ -NH-; During the ceremony, Each R ３６ , R ３６’ , R ３６’’ , R ３６’’’ , R ３９ and R ３９’ is independently H or -COOH; each r is independently 1, 2, 3, 4, 5; and each t is independently 1, 2, 3, 4, or 5; A compound, or a pharma- ceutically acceptable salt thereof.

3. BL-L ｘ ) ｋ -Chが、BL-L ３ -Ch,BL-L １ -L ３ -Ch,BL-L ３ -L ３ -L １ -L １ -L １ -L ３ -Ch,BL-L ３ -L １ -Ch,BL-L ３ -L ３ -L ３ -Ch,BL-L ３ -L ３ -L １ -L ３ -L ３ -Ch,BL-L ３ -L １ -L ３ -Ch,BL-L ３ -L ３ -AA-L １ -L ２ -L ３ -Ch,BL-L ３ -L ３ -L １ -L １ -L １ -L ２ -Ch,BL-L ３ -L ３ -L ３ -L １ -AA-Ch、BL-L ３ -L ３ -AA-Ch、BL-L ３ -L ３ -Ch,BL-L ３ -L １ -AA-Ch、BL-L ３ -L ３ -L ３ -L １ -Ch,BL-L ３ -L ３ -L ３ -L １ -L １ -Ch,BL-L ３ -L １ -L １ -L １ -L １ -AA-AA-AA-AA-Ch, BL-L ３ -AA-Ch, BL-L ３ -L １ -L １ -L １ -AA-AA-AA-AA-Ch, BL-L ３ -L ３ -L ３ -AA-Ch or BL-L ３ -L ３ -L ３ -L ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: -Ch and each AA is independently an amino acid residue.

4. BL comprises one amino acid residue covalently bonded to a pteryl group or derivative thereof, and BL-(L ｘ ) ｋ -Ch is BL-L ３ -Ch, BL-L １ -L １ -L １ -L ３ -Ch, BL-L １ -Ch, BL-L ３ -L ３ -Ch, BL-L １ -L ３ -L ３ -Ch, BL-L １ -L ３ -Ch, BL-L ３ -L ３ -AA-L １ -L ２ -L ３ -Ch, BL-L １ -L １ -L １ -L ２ -Ch, BL-L ３ -L ３ -L １ -AA-Ch, BL-L ３ -AA-Ch, BL-L １ -AA-Ch, BL-L ３ -L ３ -L １ -Ch, BL-L ３ -L １ -Ch, BL-L ３ -L ３ -L １ -L １ -Ch, BL-L ３ -L １ -L １ -Ch, BL-L １ -L １ -L １ -L １ -AA-AA-AA-AA-Ch, BL-AA-Ch, BL-L １ -L １ -L １ -AA-AA-AA-AA-Ch, or BL-L １ -L １ -L １ -L １ -L ２ -L ３ -L １ -L １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: -Ch and each AA is independently an amino acid residue.

5. When k is greater than 4, the L ｘ At least three of the following are independently 【Chemistry 7】 2. The compound of claim 1, selected from:

6. When k is greater than 4, L in formula (I) ｘ At least three of the following are independently 【Chemistry 8】 2. The compound of claim 1, selected from:

7. At least one L ｘ but, 【Chemistry 9】 2. The compound of claim 1, wherein:

8. BL-(L ｘ ) ｋ -Ch is a compound of the formula BL-L ｘ -L ａ -L ｘ -Ch, BL-L ｘ -L ｘ -L ａ -L ｘ -Ch, BL-L ｘ -L ｘ -L ａ -Ch, or BL-L ｘ -L ｘ -L ａ -L ａ -Ch, L ａ but, 【Chemistry 10】 And each L ｘ But independently, AA, L １ , or L ３ 2. The compound of claim 1, wherein:

9. BL-(L ｘ ) ｋ -Ch is a compound of the formula BL-L ａ -L ｘ -Ch, BL-L ｘ -L ａ -L ｘ -Ch, BL-L ｘ -L ａ -Ch, or BL-L ｘ -L ａ -L ａ -Ch, L ａ but, 【Chemistry 11】 And each L ｘ But independently, AA, L １ , or L ３ 2. The compound of claim 1, wherein:

10. L ａ but, 【Chemistry 12】 9. The compound of claim 8, which is: or a pharma- ceutically acceptable salt thereof.

11. L a is 【Chemistry 12】 10. The compound of claim 9, wherein:

12. At least one L ｘ but, 【Chemistry 13】 2. The compound of claim 1, wherein:

13. At least one L ｘ but, 【Chemistry 14】 2. The compound of claim 1, wherein:

14. BL-(L ｘ ) ｋ -Ch is a compound of the formula BL-L ｘ -L ｂ -L ｘ -Ch, BL-L ｘ -L ｂ -Ch, or BL-L ｘ -L ｂ -L ｂ -Ch, L ｂ but, 【Chemistry 15】 And each L ｘ But independently, AA, L １ , or L ３ 2. The compound of claim 1, wherein:

15. BL-(L ｘ ) ｋ -Ch is a compound of the formula BL-L ｂ -L ｘ -Ch, BL-L ｂ -Ch, or BL-L ｂ -L ｂ -Ch, L ｂ but, 【Chemistry 16】 And each L ｘ But independently, AA, L １ , or L ３ 2. The compound of claim 1, wherein:

16. L ｂ but, 【Chemistry 17】 14. The compound of claim 13, wherein:

17. L b is 【Chemistry 17】 15. The compound of claim 14, which is: or a pharma- ceutically acceptable salt thereof.

18. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein BL comprises a pteryl group or a derivative thereof.

19. BL is of the formula 【Chemistry 18】 (In the formula, AA is an amino acid residue; R １ and R ２ is, in each instance, independently H, halogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, -OR ７ , -SR ７ and -NR ７ R ７’ C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl and C ２ ~C ６ Each hydrogen atom in an alkynyl group can be replaced by a halogen, -OR ８ , -SR ８ , -NR ８ R ８’ , -C(O)R ８ , -C(O)OR ８ or -C(O)NR ８ R ８’ independently and optionally substituted by; R ３ , R ４ , R ５ and R ６ are each independently H, a halogen, or C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, -CN, -NO ２ , -NCO, -OR ９ , -SR ９ , -NR ９ R ９’ , -C(O)R ９ , -C(O)OR ９ and -C(O)NR ９ R ９’ C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl and C ２ ~C ６ Each hydrogen atom in an alkynyl group can be replaced by a halogen, -OR １０ , -SR １０ , -NR １０ R １０’ , -C(O)R １０ , -C(O)OR １０ or -C(O)NR １０ R １０’ independently and optionally substituted by; Each R ７ , R ７’ , R ８ , R ８’ , R ９ , R ９’ , R １０ and R １０’ are independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl or C ２ ~C ６ alkynyl; X １ is -N(R １１ )-, =N-, -N=, -C(R １１ ) = or = C (R １１ )—and X ２ is -N(R １１’ )- or =N-; X ３ is -N(R １１’’ )-, -N= or -C(R １１’ ) =; X ４ is -N= or -C=; X ５ is -N(R １２ )-or-C(R １２ ) (R １２’ )—wherein X １ is -N= or -C(R １１ )=, then Y １ is H, -OR １３ Or -SR １３ or X １ But -NR １１ -, =N- or =C(R １１ )-, then Y １ is =O; X ４ When -C=, Y ２ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, -C(O)R １４ , -C(O)OR １４ or -C(O)NR １４ R １４’ or X ４ When -N=, Y ２ does not exist; R １’ , R ２’ , R １１ , R １１’ , R １１’’ , R １２ , R １２’ , R １３ , R １４ and R １４’ are each independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, —C(O)R １５ , -C(O)OR １５ and -C(O)NR １５ R １５’ selected from the group consisting of: R １５ and R １５’ are each independently H or C １ ~C ６ is alkyl; m is 1, 2, 3 or 4; and n is 0 or 1; * represents a covalent bond to the remainder of the compound; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

20. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein m is 1.

21. X １ But -NR １１ The compound of claim 1, wherein R is -, or a pharma- ceutically acceptable salt thereof.

22. X ２ The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: is =N-.

23. Y １ The compound of claim 1 , wherein: is =O, or a pharma- ceutically acceptable salt thereof.

24. X １ But -NR １１ - and R １１ is H, or a pharma- ceutically acceptable salt thereof.

25. X ３ But -C(R １１’ 2. The compound of claim 1, wherein:

26. R １１’ is H; or a pharma- ceutically acceptable salt thereof.

27. X ４ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

28. Y ２ is H, or a pharma- ceutically acceptable salt thereof.

29. X ３ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

30. X ４ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

31. X ５ But -NR １２ 2. The compound of claim 1, wherein:

32. R １２ is H, or a pharma- ceutically acceptable salt thereof.

33. R １’ and R ２’ is H, or a pharma- ceutically acceptable salt thereof.

34. Each R １ and R ２ is H, or a pharma- ceutically acceptable salt thereof.

35. R ３ , R ４ , R ５ and R ６ is H, or a pharma- ceutically acceptable salt thereof.

36. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein n is 1.

37. BL is of the formula 【Chemistry 19】 2. The compound of claim 1, which is of the formula: wherein n is 0 or 1 and AA is an amino acid residue, or a pharma- ceutically acceptable salt thereof.

38. BL is of the formula 【Chemistry 20】 2. The compound of claim 1, which is:

39. Ch is １１１ In ９９ｍ Tc ９４ｍ Tc ６７ Ga ６６ Ga ６８ Ga ５２ Fe １６９ Er ７２ As ９７ Ru ２０３ Pb ６２ Cu ６４ Cu ６７ Cu １８６ Re １８８ Re ８６ Y ９０ Y ５１ Cr ５２ｍ Mn １７７ Lu １６１ Tb １６９ Yb １７５ Yb １０５ Rh １６６ Dy １６６ Ho １５３ Sm １４９ Pm １５１ Pm １７２ Tm １２１ Sn １１７ｍ Sn ２１３ Bi １４２ Pr １４３ Pr １９８ Au １９９ Au １２３ I １２４ I １２５ I １８ F １４９ Tb １５２ Tb １５５ Tb ４７ Sc ４４ Sc ４３ Sc ２２５ Ac ２１２ Pb ２１１ At ２２３ Ra ２２７ Th １３１ I ８２ Rb ７６ As ８９ Zr １１１ Ag １６５ Er ２２７ Ac, and ６１ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, comprising a radioactive element selected from the group consisting of Cu.

40. Ch, ６６ G.A. ６７ G.A. ６８ G.A. １７７ Lu, and ２２５ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, comprising a radioactive element selected from the group consisting of: I, Ib, Ic, Ig, IgE, IgF, IgH, IgI, IgM, IgN ...

41. Ch, 【Chemistry 21】 【Chemical 22】 and Ch is a radioactive element, Si- １８ F, B- １８ F, or Al- １８ The compound according to claim 1, or a salt thereof, which may contain F.

42. Ch, 【Chemistry 23】 and Ch is a radioactive element, Si- １８ F, B- １８ F, or Al- １８ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which may contain F.

43. BL comprises a pteryl group or a derivative thereof, and the pteryl group or a derivative thereof is 【Chemistry 24】 The compound of claim 1 , covalently bonded to a group selected from:

44. 1, 2 or 3 L ｘ independently, w is 1 or 2, and R １８ C ６ ~C １０ L is aryl １ and each hydrogen is a halogen or C １ ~C ６ The compound of claim 1 optionally substituted with alkyl.

45. 1, 2 or 3 L ｘ But independently, the formula 【Chemistry 25】 45. The compound of claim 44,

46. The compound has the formula (C1) to (C32): 【Chemistry 26】 【Chemical 27】 【Chemistry 28】 【Chemical 29】 【Chemistry 30】 2. The compound of claim 1, wherein the compound is any one of:

47. The compound is represented by the formula (C1) to (C32): 【Chemistry 31】 【Chemistry 32】 【Chemical Formula 33】 【Chemical 34】 【Chemistry 35】 and L in any one of the formulas (C1) to (C32) is a compound of any one of the formulas (C1) to (C32). ｘ L ｘ 2. The compound of claim 1 except that it is replaced by:

48. Different L ｘ one group replaced by is an AA group, and the different L ｘ are different AA groups, and the different AA groups are conservative amino acid substitutions for the AA groups; or a pharma- ceutically acceptable salt thereof.

49. - (L ｘ ) ｋ - is a group of formula (III) 【Chemical 36】 2. The compound of claim 1, comprising:

50. R １６ , R ３７ and R ３８ The compound of claim 49, wherein is H.

51. R ３９ The compound of claim 47, wherein is -COOH.

52. The compound of claim 48, wherein R 39 is -COOH.

53. The compound is 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 or a pharma- ceutically acceptable salt thereof; wherein the chelating group represented by the above structural formula is selected from a radioactive element, Si- １８ F, B- １８ F, or Al- １８ The compound of claim 1 which may contain F.

54. The compound has the formula 【Chemistry 45】 or a pharma- ceutically acceptable salt thereof.

55. The compound has the formula 【Chemistry 46】 where M is a bound radioelement and M is １７７ Lu or ２２５ 2. The compound of claim 1, wherein R is H, ...

56. The compound has the formula 【Chemistry 47】 or a pharma- ceutically acceptable salt thereof.

57. The compound has the formula 【Chemistry 48】 where M is a bound radioelement and M is １７７ Lu or ２２５ 2. The compound of claim 1, wherein R is H, ...

58. The compound has the formula 【Chemistry 49】 2. The compound of claim 1, comprising a group represented by the formula: and a carboxyl group at the β, γ, δ, ε, or ζ position relative to the carbonyl designated by "**" in the above formula; or a pharma- ceutically acceptable salt thereof.

59. PG, １８ F. ７５ B, ７６ B, ７７ B, ８０ B, ８０ｍ B, ８２ B, １２３ I, １２４ I, １２５ I, １３１ I and ２１１ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is labeled with a radioactive halogen selected from the group consisting of At.

60. 60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 59, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

61. A pharmaceutical composition for use in a method of treating an FR-expressing tumor or cell, said method comprising contacting one or more of said FR-expressing tumors or cells with an effective amount of a compound according to any one of claims 1 to 59, or a pharma- ceutical acceptable salt thereof, or an effective amount of the pharmaceutical composition according to claim 60, said compound comprising a chelating group for chelating a radioactive element.

62. 62. The pharmaceutical composition of claim 61, wherein the FR-expressing tumor or cell is in vitro, in vivo, or ex vivo.

63. 11. A pharmaceutical composition for use in a method of treating a proliferative disease in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 59, or a pharma- ceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 60, said compound comprising a chelating group that chelates a radioactive element.

64. 64. The pharmaceutical composition of claim 63, wherein the proliferative disease is cancer.

65. 65. The pharmaceutical composition of claim 64, wherein the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphatic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, and pituitary adenoma.

66. The pharmaceutical composition of claim 63, wherein the method further comprises administering to the subject an effective amount of folic acid.

67. The pharmaceutical composition of claim 63, wherein the method further comprises administering to the subject an effective amount of a folate metabolic antagonist.

68. The pharmaceutical composition described in claim 63, wherein the method further comprises administering to the subject an effective amount of a radiosensitizer.

69. 64. The pharmaceutical composition of claim 63, wherein the subject is a human.

70. 60. Use of a compound according to any one of claims 1 to 59, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.

71. 60. A compound according to any one of claims 1 to 59, or a pharma- ceutically acceptable salt thereof, for use in a method of treating cancer in a subject.

72. 61. A pharmaceutical composition for use in a method for imaging FR-expressing cells in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 59, or a pharma- ceutical acceptable salt thereof, or an effective amount of the pharmaceutical composition according to claim 60, wherein the compound comprises a metal, a radioactive element, or a radioactive halogen.

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