Radiopharmaceuticals

Abstract

This application relates generally to prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical compounds and their use in nuclear medicine for in vivo imaging of various tissues and for the treatment and / or prevention of various PSMA-expressing cancers, particularly prostate cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from Australian Provisional Patent Application No. 2022 / 902273 filed on August 11, 2022, and Australian Provisional Patent Application No. 2022 / 902274 filed on August 11, 2022, the contents of which are incorporated herein by reference in their entireties.

[0002] The present disclosure generally relates to prostate-specific membrane antigen (PSMA)-targeting compounds, including radiopharmaceuticals comprising PSMA-targeting compounds. In particular, the present disclosure relates to a compound of formula (1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which can be used to prepare a radiopharmaceutical or, once complexed with a radioisotope, can be used as a radiopharmaceutical. The present disclosure also generally relates to compositions comprising a compound of formula (1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which, when complexed with a radioisotope, relates to its use as a radiopharmaceutical in in vivo imaging of various tissues and in nuclear medicine for the treatment and / or prevention of various PSMA-expressing cancers, particularly prostate cancer. The present disclosure also generally relates to methods for preparing a compound of formula (1). [Background technology]

[0003] Prostate cancer is the most common cancer among men. One promising method for treating prostate cancer is the use of targeted radiopharmaceuticals, i.e., drugs that are labeled with radioisotopes and can target cancer cells to deliver toxic levels of radiation to cancer cells while sparing normal healthy tissue. Typically, radiopharmaceuticals designed to target prostate cancer cells are conjugated compounds that include a targeting ligand with high affinity for prostate cancer cells, optionally a linker (or spacer) such as a peptide, and a chelating moiety that can be conjugated to a radioisotope.

[0004] Prostate-specific membrane antigen (PSMA), also known as folate hydrolase I (FOLH1) and glutamate carboxypeptidase II (GCPII), is a transmembrane glycoprotein that is primarily expressed in normal human prostate epithelium but is overexpressed in prostate cancer, including metastatic cancer. PSMA is overexpressed in all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory cancers, making it a highly attractive target for imaging and treatment of PSMA-expressing cancers.

[0005] Two conjugates currently being investigated as potential radiopharmaceuticals for treating prostate cancer include the conjugate DOTA-PSMA-617 (also known as PSMA-617) and the conjugate DOTAGA-PSMA-I&T (also known as PSMA-I&T). 177 PSMA-617 and PSMA-I&T ([ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T) are currently considered two of the most promising conjugates for treating prostate cancer, [ 177 Lu]Lu-PSMA-617 was approved by the FDA on March 23, 2022, for the treatment of adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) previously treated with androgen receptor pathway blockade and taxane-based chemotherapy. However, [ 177 Lu]Lu-PSMA-I&T is 177 Compared to [Lu]Lu-PSMA-617, it exhibits higher initial uptake in tumor metastases and lower mean whole-body dose and lower dose to the lacrimal gland, but also exhibits higher uptake in the kidneys soon after injection, resulting in a longer clearance time (Schuchardt et al., Journal of Nuclear Medicine, 2022, 63(8), 1199-1207). 177 The low tumor-to-kidney ratio of [Lu]Lu-PSMA-I&T 177[Lu] represents a high risk of nephrotoxicity, which can be considered a potential dose-limiting factor for treatment with Lu-PSMA-I&T. 212 For alpha-emitting isotopes such as Pb, such high initial renal uptake represents a particular toxicity concern.

[0006] In light of the above, there is a need to identify, or at least provide the public with useful alternatives, new PSMA conjugates that exhibit improved in vivo biodistribution after injection, e.g., reduced renal uptake and / or faster renal clearance, while retaining high tumor uptake and efficacy. Summary of the Invention

[0007] The present inventors have embarked on the research and development of new PSMA conjugates. In particular, the present inventors have surprisingly found that by modifying the nature of the chelating moiety, it is possible to confine the radioisotope ( 212 Pb)) are particularly useful in 212 [Pb]Pb-PSMA-I&T. According to some embodiments or examples described herein, the PSMA conjugate compound of formula (1) has been found to exhibit good uptake in tumor tissue and reduced retention in the kidney after intravenous injection compared to other clinical candidates such as [Pb]Pb-PSMA-I&T. 212 [Pb]Pb-PSMA-I&T exhibits a much higher post-injection tumor-to-kidney ratio compared to [Pb]Pb-PSMA-I&T. According to some embodiments or examples described herein, the inventors have surprisingly found that the [Pb]Pb-PSMA-I&T 212 Pb]Pb-ADVC001,” a PSMA conjugate, HO-Glu-CO-Lys[SubA-D-Lys-D-Phe-D-Tyr(3I)-(Pent- 212We discovered that Pb-DO3AM)]-OH (chemical name 3S,7S,26S,29R,32R)-29-benzyl-32-(4-hydroxy-3-iodobenzyl)-5,13,20,28,31,34-hexaoxo-37-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazaheptatriacontane-1,3,7,26,37-pentacarboxylic acid) exhibited high specific uptake within PSMA-expressing tumors (including high tumor-to-kidney ratios) with very low uptake in other organs and control tumor sites. Other advantages associated with the disclosed compounds are also described herein.

[0008] In one embodiment, formula (1) [ka] (In the formula, n is 0 to 3, A is a PSMA-targeting ligand; X 1 ~X 3 are each independently absent, or —O—, —S—, —C(═O)—, or —C(═O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3 -, -S(=O)NR 3 -, -OS(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, L 1 and L 2 are each independently absent or a divalent linking moiety; R 1 and each R 2 is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl, each of which is optionally substituted; Each R 3is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted; R M is the formula (M-1) [ka] (In the formula, Y 1 ~Y 4 are each independently an optionally substituted -C 1~6 alkyl-, R 4 ~R 7 are each independently -C(=O)N(R 3 )2, -P(=O)(OR 3 )2, -P(=O)OR 3 (R 3 ), -P(=O)(R 3 )2, -C 1~10 AlkylC(=O)N(R 3 )2, -C 1~10 AlkylP(=O)(OR 3 )2, -C 1~10 AlkylP(=O)OR 3 (R 3 ) and -C 1~10 AlkylP(=O)(R 3 )2, or R 4 and R 6 or R 5 and R 7 One of them, together, forms -(CH2) m - forming a cross-link, each C 1~10 The alkyl is optionally substituted or R 4 ~R 7 One of the rings is L 3 or a bond connecting to the remainder of the molecule of formula (1), L 3 is absent and the ring is free from any ring heteroatom or Y 1 ~Y 4 or L3 is any ring heteroatom or Y 1 ~Y 4 a divalent linking moiety that connects the ring to the remainder of the molecule of formula (1) via one of [ka] is R M L in equation (1) 2 represents the bond that attaches m is 1 to 3), R M is optionally conjugated to a radioisotope), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0009] In one embodiment, the compound of formula (1) is: [ka]

[0010] In one embodiment, the compound of formula (1) is [ka] is selected from the group consisting of:

[0011] In one embodiment, R M teeth, 44 Sc, 47 Sc, 51 Mn, 52m Mn, 52g Mn, 55 Co, 58 Co, 58m Co, 61 Co, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 86 Y, 90 Y, 89 Zr, 111 In, 134 La, 152 EU,149 Tb, 152 Tb, 155 Tb, 161 Tb, 177 Lu, 203 Pb, 211 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac, and 227 and conjugated to a radioisotope, including a radioisotope selected from the group consisting of Th.

[0012] In another embodiment, a compound of formula (1L) [ka] (In the formula, n is 0 to 3, X 3 is absent or is -O-, -S-, -C(=O)-, or -C(=O)NR 3- , -NR 3- , -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3- , -S(=O)NR 3- , -OS(=O) 2- , -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, L 2 is absent or an uninterrupted or interrupted, optionally substituted aliphatic linker group; R 1 and each R 2 is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl, each of which is optionally substituted; Each R 3are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; The compound is optionally conjugated to a radioisotope.

[0013] In one embodiment, X 3 is absent or is -O-, -S-, -C(=O)-, or -C(=O)NR 3- , -NR 3- , -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3- , -S(=O)NR 3- , -OS(=O) 2- , -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, L 2 is absent or not interrupted, or -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-; and R 1 and each R 2 is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl; Each R 3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl; L 2 and R 1 ~R3 Each of the 8 is optionally replaced by Each R 8 are independently H, halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -NO2, -CN, -SCN, -N3, =O, -N(R 9 )2, -C(=O)N(R 9 )2, -S(=O)N(R 9 )2, -S(=O)2N(R 9 )2, -OR 9 , -SR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)OR 9 , -S(=O)2OR 9 , -S(=O)(OR 9 )2, -OS(=O)R 9 , -OS(=O)2R 9 , -OS(=O)OR9, -OS(=O)2OR 9 , -OS(=O)(OR 9 )2, -N(R 9 )C(=O)R 9 , -N(R 9 )S(=O)R 9 , -N(R 9 )C(=O)N(R 9 )2, -N(R 9 )S(=O)2R 9 , -P(=O)(OR 9 )2, -P(=O)OR 9 (R 9), -P(=O)(R 9 )2, -OP(=O)(OR 9 )2, -OP(=O)OR 9 (R 9 ) and -OP(=O)(R 9 )2, each C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 is optionally replaced by Each R 9 are independently H, C 1~6 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~6 Alkyl-3 to 10-membered carbocyclyl, and C 1~6 alkyl-3 to 10-membered heterocyclyl, and each C 1~6 Alkyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be one or more R 10 is optionally replaced by Each R 10 are independently H, halogen, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -C(=O)N(R 11 )2, -N(R 11 )C(=O)R 11 , -OR 11 , -P(=O)(OR 11 )2, -P(=O)OR 11 (R 11 ), -P(=O)(R 11 )2, C 1~6 Alkyl and -OC 1~6 is selected from the group consisting of alkyl, Each R 11 are independently H, C 1~10 Alkyl, C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 and is selected from the group consisting of alkyl-3 to 10 membered heterocyclyl.

[0014] In one embodiment, L 2 is C 1~10 Alkyl- or -C 2~10 alkyl-, and each alkyl is independently one or more R 8 is optionally replaced by

[0015] In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 and each C is optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 is optionally replaced by

[0016] In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 and optionally substituted with one or more groups selected from alkyl.

[0017] In one embodiment, X 3is selected from the group consisting of -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-.

[0018] In one embodiment, X 3 is -C(=O)NH-.

[0019] In one embodiment, the moiety -X in formula (1L) 3 -L 2 - has the structure (L-2) or (L-3): -NHC(=O)-R 19 -CH(COOH)-* (L-2) -NHC(=O)-R 19 -* (L-3) (In the formula, R 19 is one or more R 8 C optionally replaced with 1~10 Alkyl or C 2~10 is alkyl, * indicates the bond attached to the ring N in formula (1L).

[0020] In one embodiment, the moiety -X in formula (1L) 3 -L 2 - Structure (L-2): -NHC(=O)-R 19 -CH(COOH)-* (L-2) (In the formula, R 19 is one or more R 8 C optionally replaced with 1~10 Alkyl or C 2~10 is alkyl, * indicates the bond attached to the ring N in formula (1L).

[0021] In one embodiment, R 1 and R 2 is, each independently, optionally substituted alkylaryl or optionally substituted alkylheteroaryl.

[0022] In one embodiment, R 1 and R 2 are each independently optionally substituted alkylaryl.

[0023] In one embodiment, R 1 and R 2 are each independently optionally substituted benzyl.

[0024] In one embodiment, R 1 and R 2 are each independently a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 is optionally substituted with one or more groups selected from

[0025] In one embodiment, R 1 and R 2 are each independently benzyl optionally substituted with one or more groups selected from halogen, —NO 2 , —NH 2 , —CN, —SCN, —COOH, and —OH.

[0026] In one embodiment, R 1 is benzyl and R 2 is benzyl substituted with one or more groups selected from halogen, —NO 2 , —NH 2 , —CN, —SCN, —COOH, and —OH. In one embodiment, the compound of formula (1L) is: [ka]

[0027] In one embodiment, the compound of formula (1L) is [ka] is selected from the group consisting of:

[0028] In one embodiment, the compound of formula (1L) is conjugated to a radioisotope.

[0029] In one embodiment, the compound of formula (1L) is 44 Sc, 47 Sc, 51 Mn, 52m Mn, 52g Mn, 55 Co, 58 Co, 58m Co, 61 Co, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 86 Y, 90 Y, 89 Zr, 111 In, 134 La, 152 EU, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 177 Lu, 203 Pb, 211 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac, and 227 The radioisotope is conjugated to a radioisotope selected from the group consisting of Th.

[0030] In one embodiment, the compound of formula (1L) is 212 It is complexed with Pb.

[0031] In another aspect, there is provided a compound of formula (1), including any one of compound formulas (1A) to (1L) as defined herein, for use in the diagnosis, treatment, and / or prevention of PSMA-expressing cancer.

[0032] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (1), including any one of compound formulas (1A) to (1L) as defined herein, and a pharmaceutically acceptable excipient.

[0033] In another aspect, there is provided a method for treating and / or preventing PSMA-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (1), including any one of compound formulas (1A) to (1L) as defined herein, or a pharmaceutical composition as defined above.

[0034] In another aspect, there is provided the use of a compound of formula (1), including any one of compound formulas (1A) to (1L) as defined herein, or a pharmaceutical composition as defined above, for treating and / or preventing PSMA-expressing cancer.

[0035] In another aspect, there is provided the use of a compound of formula (1), comprising any one of compound formulas (1A) to (1L) as defined herein, or a pharmaceutical composition as defined above, in the manufacture of a medicament for treating and / or preventing PSMA-expressing cancer.

[0036] In one embodiment, the PSMA-expressing cancer is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC).

[0037] In another aspect, there is provided an imaging agent comprising a compound of formula (1), including any one of compound formulas (1A) to (1L) as defined herein.

[0038] In one embodiment, the compound is conjugated to a positron-emitting radioisotope or a gamma-emitting radioisotope. In one embodiment, the positron-emitting radioisotope is 68 Ga, 64 Cu, 55 Co, and 89 Zr is selected from the group consisting of

[0039] In another aspect, there is provided a diagnostic composition comprising an imaging agent as defined above and a pharmaceutically acceptable excipient.

[0040] In another aspect, there is provided a method of imaging tissue in a subject, the method comprising administering to the subject a diagnostically effective amount of an imaging agent as defined above or a diagnostic composition as defined above.

[0041] In another aspect, there is provided a use of an imaging agent as defined above or a diagnostic composition as defined above for imaging tissue in a subject.

[0042] In another aspect, there is provided an ex vivo method of imaging a tissue sample comprising a diagnostically effective amount of an imaging agent as defined above or a diagnostic composition as defined above.

[0043] In another aspect, there is provided the use of a compound as defined above or a pharmaceutical composition as defined above in the manufacture of an imaging agent for imaging tissue in a subject.

[0044] In one embodiment, the tissue is a PSMA-expressing tumor tissue. In one embodiment, the PSMA-expressing tumor tissue is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC).

[0045] In another aspect, there is provided a method for preparing a compound of formula (1), comprising any one of compound formulas (1A) to (1L), or a salt or solid supported derivative thereof, comprising coupling a compound of formula (R-1) with a compound of formula (S-1): [ka] (In the formula, RG 1 and R.G. 2 are each independently a reactive coupling group; n, A, X 1 , L 1 , X 2 , R 1 , R 2 , L 2 , and R M are described herein) A method is provided wherein the compound of formula (S-1) is optionally attached to a solid support.

[0046] In another embodiment, there is provided a method for preparing a compound of formula (1L), or a salt or solid supported derivative thereof, comprising coupling a compound of formula (R-2) with a compound of formula (S-2): [ka] (In the formula, RG 1 and R.G. 2 are each independently a reactive coupling group; n, L 2 , R 1 , and R 2 are described herein) A method is provided wherein the compound of formula (S-2) is optionally attached to a solid support.

[0047] Other aspects and embodiments related to the present disclosure are described herein. Unless specifically stated otherwise, it will be understood that each example, aspect, and embodiment of the present disclosure described herein applies by analogy to each and every other example, aspect, or embodiment. For example, each example, aspect, and embodiment of a compound of Formula (1) described herein may equally apply to one or more of the compounds, pharmaceutical compositions, imaging agents, diagnostic compositions, processes, methods, and uses of Formulas (1A)-(1L) described herein, and vice versa. For example, each of the compounds of Formulas (1A)-(1L) is within the scope of the compounds of Formula (1), and thus, substituents described herein in connection with Formula (1), where applicable, apply equally to one or more of the compounds of Formulas (1A)-(1L), and vice versa. The present disclosure should not be limited in scope by the specific examples described herein, which are intended for illustrative purposes only. Functionally equivalent substituents, compositions, methods, and processes are expressly within the scope of the present disclosure described herein. [Brief explanation of the drawings]

[0048] Embodiments of the present disclosure are further described and illustrated below, by way of example only, with reference to the accompanying drawings, in which: [Figure 1A] FIG. 1 shows the uptake and retention of [212Pb]Pb-ADVC001 in the kidney (% injected dose per gram (%ID / g) at 1 hour (green), 4 hours (blue), and 24 hours (red) after injection). [Figure 1B] FIG. 1 shows the uptake and retention (%ID / g) of [212Pb]Pb-PSMA-I&T at 1 hour (green), 4 hours (blue), and 24 hours (red) after injection. [Figure 2A] FIG. 1 shows the uptake and retention (%ID / g) of [212Pb]Pb-ADVC001 (green) and [212Pb]Pb-PSMA-I&T (blue) in the kidney 4 hours after injection. [Figure 2B]Figure 1 shows tumor:kidney ratios for 212Pb-ADVC001 (green) and [212Pb]Pb-PSMA-I&T (blue) at 1 hour, 4 hours, and 24 hours post-injection. [212Pb]Pb-ADVC001 shows high uptake and retention in PSMA-expressing tumor tissue, has very fast systemic and renal clearance, and minimal retention in kidney tissue, resulting in a higher tumor:kidney ratio compared to [212Pb]Pb-PSMA-I&T. [Figure 3] FIG. 1 shows the accumulation of [212Pb]Pb-ADVC001 over time in PSMA-expressing tumors and major organs. DETAILED DESCRIPTION OF THE INVENTION

[0049] The present disclosure describes the following various non-limiting embodiments relating to research undertaken to develop compounds that can be used as PSMA ligands.

[0050] General terminology In the following description, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration several embodiments, It is to be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present disclosure.

[0051] With respect to the definitions provided herein, unless otherwise stated or implied from context, the defined terms and phrases include the meaning provided. Unless otherwise expressly stated or apparent from context, the following terms and phrases do not exclude the meaning that the term or phrase would have acquired by one of ordinary skill in the relevant art. The definitions are provided to help describe particular embodiments and are not intended to limit the claimed invention, as the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0052] All publications discussed and / or referenced herein are incorporated herein in their entirety.

[0053] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present disclosure and is not to be construed as an admission that any or all of such matters form part of the prior art or were general general knowledge in the art relevant to the present disclosure prior to the priority date of each claim of this application.

[0054] Throughout this disclosure, unless specifically stated otherwise or unless the context requires otherwise, reference to a single step, composition of matter, group of steps, or group of compositions of matter should be construed to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps, or group of compositions of matter. Thus, as used herein, the singular forms "a," "an," and "the" include plural aspects unless the context clearly dictates otherwise. For example, reference to "a" includes two or more than just the singular, reference to "an" includes two or more than just the singular, reference to "the" includes two or more than just the singular, etc.

[0055] Those skilled in the art will understand that the disclosure herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The present disclosure also includes all and any and all combinations of the examples, steps, features, methods, hydrogels, processes, and compositions, or any two or more of such steps or features, individually or collectively referred to or shown herein.

[0056] The term "and / or", for example, "X and / or Y" shall be understood to mean either "X and Y" or "X or Y", and shall be interpreted as explicitly endorsing both meanings or either meaning.

[0057] Unless otherwise specified, terms such as "first," "second," and the like are used herein merely as labels, and are not intended to impose any sequential, positional, or hierarchical requirements on the items to which they refer. Furthermore, a reference to a "second" item does not require or preclude the presence of lower-numbered items (e.g., the "first" item) and / or higher-numbered items (e.g., the "third" item).

[0058] As used herein, the phrase “at least one of,” when used in conjunction with a list of items, means that different combinations of one or more of the listed items may be used, and that only one of the items in the list may be required. An item may be a specific object, thing, or category. In other words, “at least one of” means that any combination or number of items may be used from the list, but not all items in the list may be required. For example, “at least one of item A, item B, and item C” may mean item A, item A and item B, item B, item A, item B, and item C, or item B and item C. In some cases, “at least one of item A, item B, and item C” may mean, for example, without limitation, two of item A, one of item B, and ten of item C, four of item B, and seven of item C, or some other suitable combination.

[0059] As used herein, unless otherwise specified, the term "about" typically refers to a range of up to ±10% of the specified value, including smaller ranges therein, such as ±5% or ±1% of the specified value.

[0060] It will be understood that certain features that are described in this specification in the context of separate embodiments may also be provided in combination in a single embodiment for clarity. Conversely, various features that are described in the context of a single embodiment may also be provided separately or in any subcombination for brevity.

[0061] Throughout this specification, various aspects and components of the invention may be presented in a range format. The range format is included for convenience and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values within that range, unless specifically indicated otherwise. For example, a description of a range such as 1 to 5 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 5, 3 to 5, etc., as well as individual and partial numbers within the recited range, e.g., 1, 2, 3, 4, 4.5, 4.75, 5, etc., unless an integer is required or implied by context. This applies regardless of the breadth of the disclosed range. Where specific values are required, they are provided herein.

[0062] Throughout this specification the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0063] specific term As used herein, the term "subject" refers to any living organism susceptible to a disease or condition requiring treatment. For example, the subject can be a mammal, a primate, a livestock animal (e.g., sheep, cows, horses, pigs), a companion animal (e.g., dog, cat), or a laboratory animal (e.g., mouse, rabbit, rat, guinea pig, hamster). In one example, the subject is a mammal. In one embodiment, the subject is a human.

[0064] As used herein, the term "treating" or "treatment" includes alleviating symptoms associated with a particular disease or condition, as well as reducing and / or eliminating such symptoms. For example, as used herein, the term "treating a PSMA-expressing cancer" refers to alleviating symptoms associated with a PSMA-expressing cancer, such as prostate cancer, and / or eliminating symptoms associated with a PSMA-expressing cancer.

[0065] As used herein, the terms "prevent" or "prevention" include the prevention of a particular disorder or condition. For example, as used herein, the term "preventing a PSMA-expressing cancer" refers to preventing the onset or duration of symptoms associated with a PSMA-expressing cancer, such as prostate cancer.

[0066] As will be understood by those skilled in the art, a compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be administered in a therapeutically effective amount. The term "therapeutically effective amount," as used herein, refers to a compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, administered in an amount sufficient to alleviate or prevent to some extent one or more of the symptoms of the disorder or condition being treated. That result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. For example, one result can be the alleviation of one or more symptoms associated with a PSMA-expressing cancer, such as prostate cancer. The term "effective amount," as used herein, refers to an amount of a compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, effective to achieve a desired pharmacological effect or therapeutic improvement without undue adverse side effects. By way of example only, a therapeutically effective amount can be determined by routine experimentation, including, but not limited to, a dose-escalation clinical trial. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. In one embodiment, a prophylactically effective amount is an amount sufficient to prevent a PSMA-expressing cancer, such as prostate cancer. It is understood that an "effective amount" or a "therapeutically effective amount" may vary from subject to subject due to variations in the metabolism of the compound, as well as the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. Thus, it is not always possible to specify an exact "effective amount." However, an appropriate "effective amount" in any individual case can be determined by one of ordinary skill in the art using routine experimentation. When two or more therapeutic agents are used in combination, the "therapeutically effective amount" of each therapeutic agent may refer to the amount of the therapeutic agent that is therapeutically effective when used alone, or may refer to an adjusted (e.g., reduced) amount that is therapeutically effective in combination with one or more additional therapeutic agents.

[0067] The term "onset" of activity, as used herein, refers to the length of time following administration of a compound of Formula (1) until one or more of the symptoms of the disorder or condition being treated are alleviated or prevented to some extent. The term "duration" refers to the length of time that a therapeutic agent remains therapeutically effective, i.e., alleviates or prevents to some extent one or more of the symptoms of the disorder or condition being treated. Those skilled in the art will recognize that the onset, peak, and duration of treatment can vary depending on factors such as the patient, the patient's condition, and the route of administration.

[0068] The term "PSMA-expressing cancer", as used herein, refers to any cancer in which cancerous cells express prostate-specific membrane antigen (PSMA) and its respective metastases. Preferably, the cancer (or cancer cells) that can be treated according to the present invention is selected from prostate cancer, conventional renal cell carcinoma, transitional cell carcinoma of the bladder, testicular germ cell carcinoma, neuroendocrine carcinoma, colorectal cancer, brain tumor, and breast cancer. In a particularly preferred example, the PSMA-expressing cancer is prostate cancer or breast cancer, particularly prostate cancer. In one example, the PSMA-expressing cancer may be metastatic castration-resistant prostate cancer (mCRPC).

[0069] As used herein, the term "PSMA-targeting ligand" refers to a chemical moiety that targets PSMA.

[0070] The compounds of the present disclosure may contain chiral (asymmetric) centers, or the entire molecule may be chiral. Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are within the scope of the present disclosure.

[0071] The terms "halo" or "halogen," whether used alone or in compound words such as haloalkyl, refer to fluorine, chlorine, bromine, or iodine. Furthermore, when used in compound words such as haloalkyl, the alkyl may be partially halogenated or fully substituted with halogen atoms, which may independently be the same or different. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoropropyl, fluorobutyl, difluoromethyldifluoroethyl, trifluoromethyl, and trifluoroethyl groups. Further examples of haloalkyl groups include -CF, -CCl, and -CHCF, -CFCF, and -CHCHFCl.

[0072] As used herein, the term "alkyl," whether used alone or in compound words such as haloalkyl, cycloalkyl, alkylcycloalkyl, alkylcarbocyclyl, heteroalkyl, alkylheterocyclyl, alkylheteroaryl, alkylamido, alkylphosphonate, and alkylaryl, represents a straight-chain (i.e., linear) or branched-chain hydrocarbon group. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups. In one example, an alkyl group has 1 to 20 carbon atoms (i.e., C 1~20 In another example, alkyl is a group of 1 to 10 carbon atoms (i.e., C 1~10 In another example, an alkyl group is a group of 1 to 6 carbon atoms (i.e., C 1~6 alkyl).

[0073] As used herein, the term "heteroalkyl" refers to straight-chain (i.e., linear) or branched-chain hydrocarbon groups analogous to alkyl groups, except that one or more carbon atoms are replaced by one or more heteroatoms selected from nitrogen, sulfur, and oxygen.

[0074] As used herein, the term "alkenyl" refers to a straight-chain (i.e., linear) or branched-chain unsaturated hydrocarbon group containing at least one carbon-carbon double bond. Examples of alkenyl groups include ethylene, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl groups. In one example, an alkenyl group is a group of 2 to 20 carbon atoms (i.e., C 2~20 In another example, alkenyl is a group of 2 to 10 carbon atoms (i.e., C 2~10 In another example, an alkenyl group is a group of 2 to 6 carbon atoms (i.e., C 2~6 alkenyl).

[0075] As used herein, the term "alkynyl" refers to a straight-chain (i.e., linear) or branched-chain unsaturated hydrocarbon group containing at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl groups. In one example, an alkynyl group is a group of 2 to 20 carbon atoms (i.e., C 2~20 In one example, an alkynyl group is a group of 2 to 10 carbon atoms (i.e., C 2~10 In another example, an alkynyl group is a group of 2 to 6 carbon atoms (i.e., C 2~6 alkynyl).

[0076] As used herein, the term "haloalkyl" refers to an alkyl group having at least one halogen substituent, where "alkyl" and "halogen" are defined above. For example, a haloalkyl group can have at least one, two, or three halogen substituents. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoropropyl, fluorobutyl, difluoromethyldifluoroethyl, trifluoromethyl, and trifluoroethyl groups. Further examples of haloalkyl groups include -CF3, -CCl3, and -CH2CF3, -CF2CF3, and -CH2CHFCl. In one example, a haloalkyl group is a group of 1 to 20 carbon atoms (i.e., C 1~20 In one example, a haloalkyl group is a group of 1 to 10 carbon atoms (i.e., C 1~10 In another example, a haloalkyl group is a group of 1 to 6 carbon atoms (i.e., C 1~6 haloalkyl).

[0077] As used herein, the terms "carbocyclyl" and "carbocycle," whether used alone or in compound words such as alkylcarbocyclyl, refer to a monocyclic or polycyclic ring system in which the ring atoms are all carbon atoms, e.g., from about 3 to about 20 carbon atoms, and which may be aromatic, non-aromatic, saturated, or unsaturated, and which may be substituted and / or contain fused rings. In one embodiment, a carbocyclyl group is a group of 3 to 20 carbon atoms (i.e., C 3~20 In another example, the carbocyclyl group is a group of 3 to 10 carbon atoms (i.e., C 3~10and (f-membered carbocyclyl). Examples of such groups include aryl groups such as phenyl, naphthyl, anthracenyl, or fluorenyl, saturated groups such as cycloalkyl and cycloalkenyl groups, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl groups, or fully or partially hydrogenated phenyl, naphthyl, and fluorenyl. It should be understood that polycyclic ring systems include bicyclic and tricyclic ring systems.

[0078] As used herein, the term "cycloalkyl," whether used alone or in compound words such as alkylcycloalkyl, refers to monocyclic or polycyclic carbocyclic ring systems of various sizes, e.g., from about 3 to about 20 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl. Polycyclic ring systems are understood to include bicyclic and tricyclic ring systems.

[0079] As used herein, the term "heterocyclyl," whether used alone or in compound words such as alkylheterocyclyl, refers to a monocyclic or polycyclic ring system in which the ring atoms are provided by a combination of at least two different elements, typically carbon and one or more of nitrogen, sulfur, and oxygen, and the ring system may be a "heteroaryl" group, aromatic, such as non-aromatic, saturated, or unsaturated, and may be substituted and / or contain fused rings. Suitable nitrogen-atom-containing heterocyclyl groups include the corresponding N-oxides. In one example, a heterocyclyl group is a group of 3 to 20 atoms (i.e., a 3- to 20-membered heterocyclyl). In another example, a heterocyclyl group is a group of 3 to 10 atoms (i.e., a 3- to 10-membered heterocyclyl). The heteroatom may preferably be N, O, or S. Examples of monocyclic non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and azepanyl. Examples of bicyclic heterocyclyl groups in which one ring is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzazepanyl. Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl (e.g., a radical derived from pyridine), triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl. Examples of bicyclic aromatic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole.It should be understood that polycyclic ring systems include bicyclic and tricyclic ring systems.

[0080] As used herein, amino acids may be referred to by their full name, three letter code, or one letter code, all of which would be understood by one of skill in the art.

[0081] As will be understood, an "aromatic" group refers to a cyclic group having 4m+2 pi electrons, where m is an integer greater than or equal to 1. As used herein, "aromatic" is used interchangeably with "aryl" to refer to an aromatic group, regardless of the valency of the aromatic group.

[0082] As used herein, the term "aryl," whether used alone or in compound words such as alkylaryl, refers to a monocyclic (e.g., phenyl) or polycyclic (e.g., naphthyl) aromatic carbocyclic ring system. In one example, an aryl group is a group of 3 to 20 carbon atoms (i.e., an aromatic 3- to 20-membered carbocyclyl). In another example, an aryl group is a group of 3 to 10 carbon atoms (i.e., an aromatic 3- to 10-membered carbocyclyl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, or fluorenyl. Polycyclic ring systems are understood to include bicyclic and tricyclic ring systems. As used herein in connection with the term aryl, the term "aralkyl" refers to an alkyl group in which a hydrogen atom is replaced by an aryl group as a substituent. Examples of alkylaryl groups include, but are not limited to, optionally substituted benzyl (e.g., CH2-phenyl).

[0083] As used herein, the term "heteroaryl," whether used alone or in compound words such as alkylheteroaryl, refers to a monocyclic or polycyclic aromatic ring system in which the ring atoms are provided by a combination of at least two different elements, typically carbon and one or more of nitrogen, sulfur, and oxygen, and which may be optionally substituted and / or contain fused rings. Suitable nitrogen-containing heteroaryl groups include the corresponding N-oxides. In one example, a heteroaryl group is a group of 3 to 20 atoms (i.e., a 3- to 20-membered heteroaryl). In another example, a heteroaryl group is a group of 3 to 10 atoms (i.e., a 3- to 10-membered heteroaryl). Examples of monocyclic heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl. Examples of bicyclic heteroaryl groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole. All positional isomers are contemplated, for example, 2-pyridyl, 3-pyridyl, and 4-pyridyl. It should be understood that polycyclic ring systems include bicyclic and tricyclic ring systems.

[0084] As used herein, the term "divalent linking moiety" refers to any divalent group that is capable of linking, joining, bonding, or attaching two chemical moieties.

[0085] "-C(=O)-" represents a carbonyl linker group.

[0086] "--C(.dbd.O)O--" represents an ester linking group.

[0087] "--C(.dbd.O)S--" represents a thioester linking group.

[0088] "-C(=O)NH-" or "-C(=O)NR-" represents an amide linker group.

[0089] "-S(=O)2-" represents a sulfone linker group.

[0090] "--S(=O)NH--" or "--S(=O)NR--" represents a sulfinamide linker group.

[0091] "-S(=O)2NH-" or "-S(=O)2NR-" represents a sulfonamide linker group.

[0092] "-OS(=O)2-" represents a sulfonate ester linker group.

[0093] "-O-" represents an ether linker group.

[0094] "-NH-" or "-NR-" represents an amine linker group.

[0095] "-S-" represents a sulfide linker.

[0096] "-NHC(=S)NH-" or "-N(R)C(=S)N(R)-" represents a thiourea linker group.

[0097] "-NHC(=O)NH-" or "-N(R)C(=O)N(R)-" represents a urea linking group.

[0098] "-(CH2) m "-" represents an alkylene linking group containing an alkylene bridge having a defined number ("m") of methylene (-CH2-) units.

[0099] Unless otherwise stated or structurally indicated, it is understood that the orientation of the linker groups described above and herein in the compounds of Formula (1) is not defined, i.e., the linker group may be attached to either side in the compounds of Formula (1).

[0100] As used herein, the term "saturated" refers to a group in which all available valence bonds of the backbone atoms are attached to other atoms. Representative examples of saturated groups include, but are not limited to, butyl, cyclohexyl, piperidine, and the like.

[0101] As used herein, the term "unsaturated" refers to a group in which at least one valence bond of two adjacent skeletal atoms is not attached to any other atom. Representative examples include, but are not limited to, alkenes (e.g., -CH-CHCH=CH), phenyl, pyrrole, etc.

[0102] As used herein, the term "optionally substituted" means that a functional group is substituted or unsubstituted at any available position.

[0103] As used herein, the term "substituted" refers to a group having one or more hydrogen or other atoms removed from a carbon or suitable heteroatom and replaced with a further group (i.e., a substituent).

[0104] As used herein, the term "unsubstituted" refers to a group that does not have any additional groups attached to it or substituted for it.

[0105] The present disclosure relates to compounds of formula (1) and pharmaceutically acceptable salts thereof. Salts can be formed for embodiments of compounds of formula (1) that contain suitable acidic or basic groups. Suitable salts of compounds of formula (1) include those formed with organic or inorganic acids or bases.

[0106] As used herein, the phrase " pharmaceutically acceptable salt " refers to a pharmaceutically acceptable organic or inorganic salt. Exemplary acid addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salt. Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts, such as potassium and sodium salts, alkaline earth metal salts, such as calcium and magnesium salts, and salts with organic bases, such as dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines, such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl, or dimethylpropylamine, or mono-, di-, or trihydroxy lower alkylamines, such as mono-, di-, or triethanolamine. Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. A counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, pharmaceutically acceptable salts may have more than one charged atom in their structure. Examples in which multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counter ions. It will also be understood that non-pharmaceutically acceptable salts are included within the scope of the present disclosure, since they may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transportation. In one example, the compound of formula (1) is an acetate salt.

[0107] Those skilled in the art of organic and / or medicinal chemistry will understand that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." As used herein, the phrase "pharmaceutically acceptable solvate" or "solvate" refers to an association of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. It will be understood that the present disclosure encompasses solvated forms, including hydrates, of the compound of formula (1) and its salts.

[0108] Those skilled in the art of organic and / or medicinal chemistry will understand that the compound of formula (1) and its salts may exist in amorphous or crystalline form, and it will be understood that the present disclosure encompasses all forms and polymorphs of the compound of formula (1) and its salts.

[0109] As used herein, the term "stereoisomers" refers to compounds that have the same molecular formula and arrangement of bonded atoms (i.e., atom connectivity), but differ in the three-dimensional orientation of their atoms in space. As used herein, the term "enantiomers" refers to two compounds that are stereoisomers in that they are non-superimposable mirror images of each other. The relevant stereocenters may be designated as (R)- or (S)-configuration.

[0110] Compound of formula (1) The present disclosure provides a compound of formula (1) according to any of the following embodiments or examples: [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0111] In the above formula (1), n may be 0 or 1, 2, 3 or more. For example, n may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, n may be in a range provided by any of these values, including a range selected from 0 to 10, 0 to 8, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In one embodiment, n may be 0 to 3. In one embodiment, n may be 1 or more, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one embodiment, n may be 1 to 3, 1 or 2, or 1. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. When n is 0, R 1 The central carbon atom attached to X 3 It will be understood that there is a directed bond between

[0112] In one embodiment, n is 1 and the compound of formula (1) has the formula (1A): [ka] (In the formula, A, L 1 , L 2 , X 1 , X 2 , X 3 , R 1 , R 2 and R M is as described herein).

[0113] X 1 ~X 3 In the above formula (1), X 1 ~X 3 are each independently absent, or —O—, —S—, —C(═O)—, or —C(═O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3 -, -S(=O)NR 3-, -OS(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, and R 3 is as described herein. That is, X 1 does not exist, -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3 -, -S(=O)NR 3 -, -OS(=O)2-, -N(R 3 )C(=S)N(R 3 )- or -N(R 3 )C(=O)N(R 3 )-. Similarly, X 2 does not exist, -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3 -, -S(=O)NR 3 -, -OS(=O)2-, -N(R 3 )C(=S)N(R 3 )- or -N(R 3 )C(=O)N(R 3 )- may be X 3 does not exist, -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3 -, -S(=O)NR 3 -, -OS(=O)2-, -N(R 3 )C(=S)N(R 3 )- or -N(R 3 )C(=O)N(R 3 )- may also be used.

[0114] Unless otherwise stated or structurally indicated, X in compounds of formula (1) 1 , X2 , and X 3 It should be understood that the orientation of X, if any, is not defined. 1 , X 2 , and X 3 When present, X may be attached to either side of the compound of formula (1). For example, in the above formula (1), X 2 is —C(═O)NH— (i.e., an amide bond), the compound of formula (1) is [ka] It may have a structure selected from:

[0115] X 1 is not present, a bivalent linking moiety, e.g., L, can be provided between the PSMA targeting ligand A and the remainder of the molecule of Formula (1). 1 , X 2 and R 1 It will be understood that there are direct bonds, including direct bonds to any one of the carbons attached to X. 2 If there is no L 1 and X 1 Depending on whether or not R 1 and the carbon atom attached to L 1 , X 1 It will be understood that there is a direct bond between X and any one of the PSMA targeting ligands A. 3 is not present, n is 0 or 1 or more, and L 2 Depending on whether or not R 1 or R 2 and a divalent linking moiety L attached to 2 or R M It will be understood that there is a direct bond between

[0116] In one embodiment, X 1 and X 2 , X 1 and X 3 , or X 2 and X 3 are different (e.g., X1 is -C(=O)NH-, and X 2 is -NHC(=O)NH-). In other words, X 1 and X 2 , X 1 and X 3 , or X 2 and X 3 are selected independently of each other. 1 ~X 3 are the same (e.g., X 1 ~X 3 each is present and is -C(=O)NH-).

[0117] In one embodiment, X 1 ~X 3 are present, each independently representing —O—, —S—, —C(═O)—, or —C(═O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 In one embodiment, X is selected from the group consisting of 1 ~X 3 are -C(=O)NR 3 -It is.

[0118] In one embodiment, X 1 exists, -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 In one embodiment, X is selected from the group consisting of 1 is -C(=O)NR 3 -It is.

[0119] In one embodiment, X 2exists, -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 In one embodiment, X is selected from the group consisting of 2 is -C(=O)NR 3 -It is.

[0120] In one embodiment, X 3 exists, -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 In one embodiment, X is selected from the group consisting of 3 is -C(=O)NR 3 In one embodiment, X 3 is absent or is -O-, -S-, -C(=O)-, or -C(=O)NR 3- , -NR 3- , -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3- , -S(=O)NR 3- , -OS(=O) 2- , -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 In one embodiment, X is selected from the group consisting of 3 is present and is selected from the group consisting of -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-. 3is —C(═O)O— or —C(═O)NH—. In one embodiment, X 3 is -C(=O)NH-.

[0121] In the above formula (1), X 1 ~X 3 one or more of the following may be independently —C(═O)NR 3 -, -NR 3 -, -N(R 3 )C(=S)N(R 3 )- or -N(R 3 )C(=O)N(R 3 )-, then each R 3 may be independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, alkylheterocyclyl, each of which is optionally substituted. In one embodiment, X 1 ~X 3 one or more of the following may be independently —C(═O)NR 3 -, -NR 3 -, -N(R 3 )C(=S)N(R 3 )- or -N(R 3 )C(=O)N(R 3 )-, then each R 3 are independently H and C 1~10 In one embodiment, X may be selected from the group consisting of alkyl. 1 ~X 3 one or more of the following may be independently —C(═O)NR 3 -, -NR 3 -, -N(R 3 )C(=S)N(R 3 )- or -N(R 3 )C(=O)N(R 3 )-, then each R 3 is H.

[0122] In one embodiment, X 1 ~X 3are present and each independently selected from the group consisting of -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-. 1 ~X 3 exist, each being —C(═O)NH—.

[0123] In one embodiment, X 1 is selected from the group consisting of -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-. In one embodiment, X 1 is -C(=O)NH-.

[0124] In one embodiment, X 2 is selected from the group consisting of -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-. In one embodiment, X 2 is -C(=O)NH-.

[0125] In one embodiment, X 2 is selected from the group consisting of -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-. In one embodiment, X 3 is -C(=O)NH-.

[0126] In one embodiment, X 1 ~X 3 are -C(=O)NR 3 and the compound of formula (1) is a compound of formula (1B): [ka] (In the formula, n, A, L 1 , L 2 , R1 , R 2 , and R M is as described herein).

[0127] L 1 and L 2 In the above formula (1), L 1 and L 2 represent linker moieties, each independently being absent or a divalent linking moiety. 1 may be absent or a divalent linking moiety. Unless otherwise stated or structurally indicated, L in compounds of formula (1) 1 and L 2 It should be understood that the orientation of, if any, L is not defined. 1 and L 2 When present, L may be attached to either side in the compound of formula (1). 1 If does not exist, X 1 and X 2 Depending on whether or not X exists, 2 and R 1 , X 1 It will be understood that there is a direct bond between L and any one of the carbon atoms attached to PSMA targeting ligand A. Similarly, L 2 If does not exist, X 3 Depending on whether or not R M and X 3 , R 2 A carbon atom attached to (R 2 If there are multiple carbons attached to [i.e., n is 2 or 3], the bond is R 1 R furthest from the carbon atom attached to 2 (relating to the carbon atom attached to the atom), and R 1 It will be understood that there is a direct bond between any one of the carbon atoms attached to n, and n is 0, 1, 2, or 3, etc.

[0128] In one embodiment, L 1 and L 2 are different (e.g., L1 is a C interrupted by one or more groups selected from -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH 1~20 alkyl-, and L 2 is C 1~10 alkyl-, and each C 1~20 Alkyl and C 1~10 The alkyl is optionally substituted.

[0129] In one embodiment, L 1 and L 2 are each independently an uninterrupted or interrupted, optionally substituted aliphatic linker group. As used herein, the term "aliphatic linker group" refers to a divalent linking moiety in which the atoms forming the linking moiety are joined by single, double, or triple bonds to form a non-aromatic linking moiety (e.g., does not contain any aromatic ring structures within the backbone of the linking moiety). In one embodiment, L 1 is present, uninterrupted or interrupted, optionally replaced -C 1~30 In one embodiment, L 1 is uninterrupted or interrupted, optionally replaced -C 1~20 It is alkyl-.

[0130] In one embodiment, L 2 is absent or is an uninterrupted or interrupted, optionally substituted aliphatic linker group. 2 is an uninterrupted or interrupted, optionally substituted aliphatic linker group. In one embodiment, L 2 is absent or not interrupted, or -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R3 )C(=O)N(R 3 )-. In one embodiment, L 2 is present, uninterrupted or interrupted, optionally replaced -C 1~20 In one embodiment, L 2 is uninterrupted or interrupted, optionally replaced -C 1~10 It is alkyl-.

[0131] L 1 and / or L 2 If present in either 1~30 Alkyl, C 1~20 Alkyl or C 1~10 The alkyl may be uninterrupted or interrupted and may be optionally substituted. In one embodiment, each C 1~30 Alkyl, C 1~20 Alkyl or C 1~10 The alkyl may be uninterrupted or may be -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, and optionally substituted. In one embodiment, each C 1~30 Alkyl, C 1~20 Alkyl or C 1~10 The alkyl can be uninterrupted or interrupted with one or more groups selected from -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-, and can be optionally substituted. In one embodiment, each C 1~30 Alkyl, C 1~20 Alkyl or C 1~10The alkyl may be interrupted by a total of 1 to 10, 1 to 5, or preferably 1 to 3 groups, each interruption being independently -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, optionally substituted.

[0132] In one embodiment, L 1 is uninterrupted or interrupted by one or more groups selected from -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH, and optionally substituted -C 1~20 In one embodiment, L 2 -C 1~10 Alkyl- or -C 2~10 alkyl- and optionally substituted. In one embodiment, L 2 -C 2~10 alkyl- and optionally substituted. In one embodiment, L 2 -C 1~10 alkyl- and optionally substituted. In one embodiment, L 1 is one or more -C(=O)NR 3 -(e.g., -C(=O)NH-) -C interrupted by an amide bond 1~20 alkyl- and C 1~20 Alkyl is one or more R 8 In one embodiment, L 1 has a total of 1 to 5, preferably 1 to 3, and more preferably 1 to 2 -C(=O)NR in its skeleton. 3 It contains an - (eg, -C(=O)NH-) amide bond interruption and is optionally substituted.

[0133] In one embodiment, L 1and L 2 Each of the groups may be optionally substituted. 1 and L 2 are each one or more R 8 In one embodiment, L 2 is one or more R 8 In one embodiment, L 2 -C 1~10 Alkyl- or -C 2~10 alkyl- and one or more R 8 In one embodiment, L 2 -C 2~10 alkyl- and one or more R 8 In one embodiment, L 2 -C 1~10 alkyl- and one or more R 8 Optionally replaced by L 1 or L 2 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0134] In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 In one embodiment, L is optionally substituted with one or more groups selected from alkyl. 2 is C 2~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 In one embodiment, L is optionally substituted with one or more groups selected from alkyl. 2 is C 1~10 Alkyl, C 2~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 and optionally substituted with one or more groups selected from alkyl.

[0135] In one embodiment, L 2 contains a chiral center. In one embodiment, L 2 is one or more R 8 -C replaced with 1~20 Alkyl- or -C 1~10 alkyl-, and R 8 At least one carbon attached to L forms a chiral center. 2 is one or more R 8 -C replaced with 1~10 alkyl-, and R 8 At least one carbon attached to L forms a chiral center. One skilled in the art will understand that a "chiral center" refers to a tetravalent carbon atom having four different substituents thereon, or three different substituents and a hydrogen. While not intended to limit the scope of any of the aspects, embodiments, or examples described herein, L 2 It is believed that the presence of a chiral center within may contribute to the PSMA affinity of compounds of formula (1).

[0136] In one embodiment, L 2 is one or more R 8 -C replaced with 1~20 Alkyl- or -C 1~10 In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 substituted with one or more groups selected from alkyl, 1~20 Alkyl- or -C 1~10 In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 substituted with one or more groups selected from alkyl, 1~20 Alkyl- or -C 1~10 In one embodiment, L 2 is C1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 substituted with one or more groups selected from alkyl, 1~20 Alkyl- or -C 1~10 It is alkyl-.

[0137] In one embodiment, L 2 is one or more R 8 -C replaced with 1~10 In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 substituted with one or more groups selected from alkyl, 1~10 In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 substituted with one or more groups selected from alkyl, 1~10 In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 substituted with one or more groups selected from alkyl, 1~10 It is alkyl-.

[0138] In accordance with the above, in a preferred embodiment, the moiety -X of formula (1) 1 -L 1 -X 2 - is the structure (L-1): -NHC(=O)-R 19 -C(=O)NH-R 20 -CH(COOH)-NH-C(=O)-* (L-1) (where * represents R in formula (1) 1 (showing the bond attached to the carbon atom bearing the atom).

[0139] In accordance with the above, in a preferred embodiment, the moiety -X of formula (1) 3 -L 2 - has the structure (L-2) or (L-3): -NHC(=O)-R 19 -CH(COOH)-* (L-2) -NHC(=O)-R 19 -* (L-3) (where * represents R in formula (1) M (showing the bond attached to the

[0140] In some embodiments, R 19 and R 20 each independently represents an optionally substituted C 1~20 In some embodiments, R 19 and R 20 each independently represents an optionally substituted C 1~10 In some embodiments, R 19 and R 20 each independently represents one or more R 8 In one embodiment, R 19 and R 20 is unsubstituted. R 19 or R 20 One or more R 8 It will be understood that when a group is not substituted with one or more hydrogen atoms remain at the unsubstituted position.

[0141] In one embodiment, the moiety -X in formula (1L) 3 -L 2 - has the structure (L-2) or (L-3): -NHC(=O)-R 19 -CH(COOH)-* (L-2) -NHC(=O)-R 19 -* (L-3) wherein * indicates the bond attached to the ring N in formula (1L).

[0142] In some embodiments, R 19 is C 1~20 In some embodiments, R 19 is C 1~10 In some embodiments, R 19 is C 2~20 In some embodiments, R 19 is C 2~10 In some embodiments, R 19 is C 1~10 Alkyl or C 2~10 In some embodiments, R 19 is one or more R 8 In one embodiment, R 19 is unsubstituted. R 19 One or more R 8 It will be understood that when a group is not substituted with one or more hydrogen atoms remain at the unsubstituted position.

[0143] In one embodiment, the moiety -X of formula (1L) 3 -L 2 has the structure (L-2) or (L-3), and the carbon atom attached to the ring N of formula (1L) is a chiral center. While not intending to limit the scope of any of the aspects, embodiments, or examples described herein, it is believed that the presence of a chiral center at the carbon atom attached to the ring N may contribute to the PSMA affinity of compounds of formula (1).

[0144] In accordance with the above, in one embodiment, the moiety -X in formula (1L) 3 -L 2 - Structure (L-2): -NHC(=O)-R 19 -CH(COOH)-* (L-2) It has.

[0145] R 1 and R 2 Without intending to limit the scope of any of the aspects, embodiments, or examples described herein, R 1and / or R 2 It is believed that R may affect the binding affinity of the compound of formula (1) to PSMA through aromatic stacking interactions with the arene binding site on PSMA. 1 and each R 2 is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl, each of which is optionally substituted, i.e., R 1 may be selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl, each of which is optionally substituted. Similarly, R 2 R may be selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl, each of which is optionally substituted. 1 and R 2 may be the same (e.g., R 1 and R 2 are both optionally substituted alkylaryl), or R 1 and R 2 may be different (e.g., R 1 is alkylaryl, and R 2 is one or more R 8 In other words, R 1 and R 2 The substituents are selected independently of each other. 1 and R 2 are each independently optionally substituted alkylaryl or optionally substituted alkylheteroaryl. In one embodiment, R 1 and R 2 are each independently optionally substituted alkylaryl. In one embodiment, R 1 is optionally substituted alkylaryl. In one embodiment, R 1 is optionally substituted alkylheteroaryl. In one embodiment, R 2 is optionally substituted alkylaryl. In one embodiment, R 2is optionally substituted alkylheteroaryl. In one embodiment, R 1 and each R 2 is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl, i.e., R 1 may be selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl. 2 may be selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl. 1 and R 2 each independently represents an optionally substituted 3- to 10-membered aryl, an optionally substituted C 1~10 alkyl-3 to 10-membered aryl, optionally substituted 3 to 10-membered heteroaryl, or optionally substituted C 1~10 alkyl-3 to 10 membered heteroaryl, i.e., R 1 is an optionally substituted 3- to 10-membered aryl, optionally substituted C 1~10 alkyl-3 to 10-membered aryl, optionally substituted 3 to 10-membered heteroaryl, or optionally substituted C 1~10 alkyl-3-10 membered heteroaryl. Similarly, R 2 is an optionally substituted 3- to 10-membered aryl, optionally substituted C 1~10 alkyl-3 to 10-membered aryl, optionally substituted 3 to 10-membered heteroaryl, or optionally substituted C 1~10 In one embodiment, R 1 is an optionally substituted 3-10 membered aryl. In one embodiment, R 1 is optionally replaced by C 1~10 alkyl-3 to 10 membered aryl. In one embodiment, R 1 is an optionally substituted 3-10 membered heteroaryl. In one embodiment, R 1 is optionally replaced by C 1~10alkyl-3 to 10 membered heteroaryl. In one embodiment, R 2 is an optionally substituted 3-10 membered aryl. In one embodiment, R 2 is optionally replaced by C 1~10 alkyl-3 to 10 membered aryl. In one embodiment, R 2 is an optionally substituted 3-10 membered heteroaryl. In one embodiment, R 2 is optionally replaced by C 1~10 The heteroaryl or heteroaryl group of the alkylheteroaryl may be selected from the group consisting of pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl, each of which is optionally substituted.

[0146] In one embodiment, R 1 and R 2 are each independently an optionally substituted aryl or an optionally substituted alkylaryl. Preferably, the alkylaryl comprises one aryl group bonded to an alkyl group, each of which may be optionally substituted. In one embodiment, the aryl or aryl group of the alkylaryl may be independently selected from phenyl and naphthyl, e.g., 2-naphthyl. The alkyl group of the alkylaryl may be C 1~10 Alkylene group, C 1~6 It may be an alkylene group, or preferably -CH-. In one embodiment, R 1 and R 2 are each independently optionally substituted aryl, optionally substituted benzyl, or optionally substituted -CH2-naphthyl. 1 and R 2 are each independently optionally substituted benzyl. In one embodiment, R 1 and R 2are each independently benzyl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 1 is benzyl and R 2 is benzyl substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 1 is benzyl and unsubstituted, and R 2 is benzyl substituted with one or more groups selected from halogen, —NO 2 , —NH 2 , —CN, —SCN, —COOH, and —OH.

[0147] In one embodiment, R 1 and R 2 are each independently an optionally substituted benzyl, and the compound of formula (1) has the formula (1C): [ka] (In the formula, n, A, L 1 , L 2 , X 1 , X 2 , X 3 , and R M is as described herein).

[0148] In the above formula (1), R 1 and R 2 Each of may be optionally substituted. In one embodiment, R 1 and R 2 Each of the 8 In one embodiment, R 1 and R 2 are each independently a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 and each R 11 are independently as described herein. 1 or R 2 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0149] R 3 In the above formula (1), each R 3 may be independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted.

[0150] In one embodiment, X as described herein 1 ~X 3 one or more of the following may be independently —C(═O)NR 3 -, -NR 3 -, -N(R 3 )C(=S)N(R 3 )- or -N(R 3 )C(=O)N(R 3 )-, then each R 3 may be independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, alkylheterocyclyl, each of which is optionally substituted.

[0151] In one embodiment, R as described herein 4 ~R 7 However, each independently, -C 1~10 AlkylC(=O)N(R 3 )2, -C 1~10AlkylP(=O)(OR 3 )2, -C 1~10 AlkylP(=O)OR 3 (R 3 ) and -C 1~10 AlkylP(=O)(R 3 )2, each R 3 may be independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, alkylheterocyclyl, each of which is optionally substituted.

[0152] In one embodiment, the L 1 and / or L 2 , optionally replaced by C 1~30 Alkyl, optionally substituted C 1-20 alkyl or optionally substituted C 1~10 Contains alkyl, each C 1~30 Alkyl, C 1~20 Alkyl or C 1~10 The alkyl may be uninterrupted or may be —O—, —S—, —C(═O)—, or —C(═O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, each R 3 may be independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, alkylheterocyclyl, each of which is optionally substituted.

[0153] In the above formula (1), each R 3 is optionally substituted. In one embodiment, R 3 Each of the 8 R 3 One or more R 8It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0154] R M In the above formula (1), R M is a chelating moiety. In some embodiments, R M is optionally conjugated to a radioisotope as described herein. M is conjugated to a radioisotope as described herein. In some embodiments, the compound of formula (1) is optionally conjugated to a radioisotope as described herein. It will be understood that in most cases, any such conjugation will occur primarily at the chelating moiety of the compound of formula (1), such as the tetraazamacrocyclic moiety as described herein. "R M Any disclosure herein that "R is optionally conjugated to a radioisotope" should be understood to also disclose that the compound of formula (1) is optionally conjugated to that radioisotope. M Any disclosure herein that "is conjugated to a radioisotope" should be understood to also disclose that the compound of formula (1) is conjugated to that radioisotope. M can be any suitable chelating moiety capable of complexing with a radioisotope. In one embodiment, R M is a macrocyclic moiety. In one embodiment, R M is a tetraazamacrocyclic moiety. In one embodiment, R M is expressed as formula (M-1): [ka] (In the formula, [ka] is the remainder of the numerator in Eq. (1) M is a chelating moiety having the structure:

[0155] In some embodiments, L 3 is absent and the ring is not joined to any ring heteroatom (e.g., at any nitrogen atom of M-1) or Y 1 ~Y 4 Either one of or L 3 directly connected to the remainder of the molecule of formula (1) via L 3 is any ring heteroatom or Y 1 ~Y 4 is a divalent linking moiety that connects the ring to the remainder of the molecule of Formula (1) via one of 3 is absent and the ring is free from any ring heteroatom (e.g., at any nitrogen atom of M-1) or Y 1 ~Y 4 is directly connected to the rest of the molecule of formula (1) through one of the following: L 3 is not present, the remainder of the molecule of formula (1) is connected at any nitrogen atom of M-1 and the corresponding R group (e.g., R 4 ~R 7 It will be understood that any of the following groups (e.g., 3 is any ring heteroatom (e.g., at any nitrogen atom of M-1) or Y 1 ~Y 4 is a divalent linking moiety that connects the ring to the remainder of the molecule of formula (1) via one of 3 is present and connects the ring to the remainder of the molecule of formula (1) at any nitrogen atom of M-1, the corresponding R group (e.g., R 4 ~R 7 It will be understood that there is no

[0156] For compounds of formula (1), the ring (e.g., macrocyclic chelator) from L 3 , L 2 , X 3 , R 2 A carbon atom attached to (R 2 When there are multiple carbons attached to R [i.e., when n is 2 or 3], the bond is R 1 R furthest from the carbon atom attached to2 (relating to the carbon atom attached to the atom), and R 1 It will be understood that there is always a bond to any one of the carbon atoms attached to L. 3 , L 2 , X 3 , and R 2 Each of the carbon atoms attached to L may independently be absent or present, and as a result, the atom to which the ring is attached may be present at any one of L 3 , L 2 , X 3 or an atom defined by them, or R 2 carbon atom attached to, or in some cases R 1 It will be understood that the carbon atom may be attached to the

[0157] More generally, some embodiments may include groups that are absent / present (e.g., X 1 , X 2 , X 3 , L 1 , L 2 or L 3 ) and in such cases, it will be understood that a given group is linked via a covalent bond (if applicable) to the nearest existing group according to the order defined by the relevant structural formula (e.g., the structure of Formula (1), any one of Formulas (1A)-(1L), and any other structure described herein). This will be apparent to those skilled in the art, and the term "rest of the molecule" has been used in accordance with the above explanation for ease of reference when there are multiple possibilities for attachment depending on the choice of group / variable. In one embodiment, R M is a chelating moiety having the structure of formula (M-2). [ka]

[0158] In one embodiment, L 3 is absent or uninterrupted or interrupted, optionally replaced -C1~20 In one embodiment, L 3 is absent or uninterrupted or interrupted, optionally replaced -C 1~10 Alkyl-. L 3 If present, each C 1~20 Alkyl or C 1~10 The alkyl may be uninterrupted or interrupted and optionally substituted. In one embodiment, each C 1~20 Alkyl or C 1~10 The alkyl may be uninterrupted or may be -O-, -S-, -C(=O)-, -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, and optionally substituted. In one embodiment, each C 1~20 Alkyl or C 1~10 The alkyl can be uninterrupted or interrupted with one or more groups selected from -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-, and can be optionally substituted. In one embodiment, each C 1~20 Alkyl or C 1~10 The alkyl is uninterrupted and optionally substituted. In one embodiment, L 3 is optionally substituted. In one embodiment, L 3 is one or more R 8 L 3 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0159] In some embodiments, Y 1 ~Y4 are each independently an optionally substituted -C 1~6 In some embodiments, Y 1 ~Y 4 are each independently an optionally substituted -C 2~6 In some embodiments, Y 1 ~Y 4 are each independently an optionally substituted -C 2~4 In some embodiments, Y 1 ~Y 4 are each independently an optionally substituted -C 2~3 alkyl-. Y 1 ~Y 4 Each alkyl in Y may be optionally substituted. 1 ~Y 4 Each alkyl in 8 Y 1 ~Y 4 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0160] In some embodiments, R 4 ~R 7 are each independently -C(=O)N(R 3 )2, -P(=O)(OR 3 )2, -P(=O)OR 3 (R 3 ), -P(=O)(R 3 )2, -C 1~10 AlkylC(=O)N(R 3 )2, -C 1~10 AlkylP(=O)(OR 3 )2, -C 1~10 AlkylP(=O)OR 3 (R 3 ) and -C 1~10 AlkylP(=O)(R 3 )2, or R 4 and R 6 or R5 and R 7 One of them, together, forms -(CH2) m - forming a cross-link, each C 1~10 The alkyl is optionally substituted or R 4 ~R 7 is a ring L 3 or a bond connecting to the remainder of the molecule of formula (1), and m is 1 to 3, preferably 2.

[0161] In some embodiments, R 4 ~R 7 are each independently -C(=O)N(R 14 )2, -P(=O)(OR 14 )2, -P(=O)OR 3 (R 14 ), -P(=O)(R 14 )2, -C 1~10 AlkylC(=O)N(R 14 )2, -C 1~10 AlkylP(=O)(OR 14 )2, -C 1~10 AlkylP(=O)OR 14 (R 14 ) and -C 1~10 AlkylP(=O)(R 14 )2, or R 4 and R 6 or R 5 and R 7 One of them, together, forms -(CH2) m - forming a cross-link, each C 1~6 The alkyl is optionally substituted or R 4 ~R 7 is a ring L 3 or a bond connecting to the remainder of the molecule of formula (1), and m is 1 to 3, preferably 2.

[0162] In some embodiments, R 4 ~R 7 are each independently -C(=O)NH2, -P(=O)(OH)2, -P(=O)(OH)H, -P(=O)(OH)OC 1~6 Alkyl, -C1~6 AlkylC(=O)NH2, -C 1~6 AlkylP(=O)(OH)2, -C 1~6 Alkyl-P(=O)(OH)H and -C 1~6 Alkyl-P(=O)(OH)OC 1~6 alkyl, or R 4 and R 6 or R 5 and R 7 One of them, together, forms -(CH2) m - forming a cross-link, each C 1~6 The alkyl is optionally substituted or R 4 ~R 7 is a ring L 3 or a bond connecting to the remainder of the molecule of formula (1), and m is 1 to 3, preferably 2.

[0163] In some embodiments, R 4 ~R 7 are each independently -C(=O)N(R 14 )2 and -C 1~10 AlkylC(=O)N(R 14 )2, or R 4 and R 6 or R 5 and R 7 One of them, together, forms -(CH2) m - forming a bridge, or R 4 ~R 7 is a ring L 3 or a bond connecting to the remainder of the molecule of formula (1), and m is 1 to 3, preferably 2.

[0164] In some embodiments, R 4 ~R 7 are each independently -C(=O)NH2 and -C 1~6 alkyl-C(=O)NH2, or R 4 and R 6 or R 5 and R 7 One of them, together, forms -(CH2)m - forming a bridge, or R 4 ~R 7 is a ring L 3 or a bond connecting to the remainder of the molecule of formula (1), and m is 1 to 3, preferably 2. In some embodiments, each R 4 ~R 7 is optionally substituted. In some embodiments, each R 4 ~R 7 is one or more R 8 R 4 ~R 7 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0165] In some embodiments, R M are expressed by the formulas (M-1A) to (M-1D): [ka] (In the formula, [ka] is R M represents the bond attaching R to the remainder of the molecule of formula (1), r is 0 or 1, and R 4 ~R 7 is a chelating moiety having a structure selected from the group consisting of:

[0166] In some embodiments, R 12 and R 13 are each independently H, -C(=O)OR 14 , -C(=O)N(R 14 )2, -C 1~6 AlkylC(=O)OR 14 , and -C 1~6 AlkylC(=O)N(R 14 )2, -P(=O)(OR 14 )2-P(=O)OR 14 (R 14 ), -P(=O)(R 14 )2, -C1~6 AlkylP(=O)OR 14 (R 14 ) and -C 1~6 AlkylP(=O)(R 14 )2, each C 1~6 The alkyl is optionally substituted or R 12 and R 13 taken together form an optionally substituted heterocyclyl. In some embodiments, R 12 and R 13 are each independently H, -C(=O)OR 14 , -C(=O)N(R 14 )2, -C 1~6 AlkylC(=O)OR 14 , and -C 1~6 AlkylC(=O)N(R 14 )2, each C 1~6 The alkyl is optionally substituted or R 12 and R 13 taken together form an optionally substituted heterocyclyl. In some embodiments, R 12 and R 13 are each independently —C(═O)OH or —C(═O)NH2.

[0167] In the above formula (1), R 12 or R 13 Each C 1~6 The alkyl may be optionally substituted. In one embodiment, R 12 or R 13 Each C 1~6 Alkyl is one or more R 8 R 12 or R 13 C 1~6 R with one or more alkyl 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0168] In some embodiments, each R 14 are independently H, C 1~10 Alkyl, C2~10 Alkenyl, C 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 alkyl-3- to 10-membered heterocyclyl, each alkyl, alkenyl, alkynylcarbocyclyl, and heterocyclyl being selected from the group consisting of, for example, one or more R 8 is optionally replaced by R 14 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0169] In some embodiments, R M are expressed as (M-1Ai)~(M-1Dii): [ka] (In the formula, [ka] is the remainder of the numerator in Eq. (1) M represents a bond attaching 12 and R 13 is a chelating moiety having a structure selected from the group consisting of:

[0170] In some embodiments, R 15 ~R 18 are each independently -C(=O)N(R 14 )2, -P(=O)(OR 14 )2, -P(=O)OR 14 (R 14 ), and -P(=O)(R 14 In some embodiments, R 15 ~R 18 are each independently -C(=O)NH2, -P(=O)(OH)2, -P(=O)(OH)H, -P(=O)(OH)OC 1~6 alkyl, wherein C 1~6Alkyl is one or more R 8 is optionally replaced by R 15 ~R 18 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0171] In some embodiments, R M is a chelating moiety having the structure of formula (M-1E), wherein: [ka] is R M represents the bond attaching to the remainder of the molecule of formula (1), [ka] R 23 and R 24 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted, or at least one R 23 and R 24 taken together form an optionally substituted heterocyclyl.

[0172] In one embodiment, R 23 and R 24 are each independently selected from H, C, 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 alkyl-3- to 10-membered heterocyclyl, or at least one R 23 and R 24 are taken together to form an optionally substituted 3- to 10-membered heterocyclyl. In some embodiments, each R 23 and R 24may independently be one or more R 8 R 23 and R 24 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0173] In one embodiment, R M is a chelating moiety having the structure of formula (M-1F), wherein: [ka] is R M represents the bond attaching the group to the remainder of the molecule of formula (1). [ka]

[0174] In one embodiment, -X in formula (1) 3 -L 2 -R M is 2(R,S)-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetamido]-5-amidopentanoic acid.

[0175] In some embodiments, R M Or the compound of formula (1) is optionally conjugated to a radioisotope. M Or exemplary radioisotopes that are optionally chelated by compounds of formula (1) include: 44 Sc, 47 Sc, 51 Cr, 51 Mn, 52m Mn, 52g Mn, 52 Fe, 55 Co, 58 Co, 58m Co, 61 Co, 56 Ni, 57 Ni, 61 Cu, 62 Cu, 64 Cu, 67 Cu,66 Ga, 68 Ga, 67 Ga, 86 Y, 89 Y, 90 Y, 89 Zr, 94m Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 134 La, 142 Pr, 143 Pr, 149 Pm, 151 Pm, 149 Ib, 152 EU, 153 Sm, 157 Gd, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 177 Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 203 Pb, 211 Pb, 212 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 225 Ac and 227 Th is an example.

[0176] In some embodiments, R M or the compound of formula (1) optionally 44 Sc, 47 Sc,51 Mn, 52m Mn, 52g Mn, 55 Co, 58 Co, 58m Co, 61 Co, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 86 Y, 90 Y, 89 Zr, 111 In, 134 La, 152 EU, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 177 Lu, 203 Pb, 211 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac, and 227 In one embodiment, R is conjugated to a radioisotope selected from the group consisting of: M is optionally 212 In one embodiment, the compound of formula (1) is optionally complexed to Pb. 212 In one embodiment, the compound of formula (1) is 212 It is complexed with Pb.

[0177] R M Alternatively, when a compound of formula (1) is conjugated to a radioisotope as described herein, the conjugate comprising the compound of formula (1) and the radioisotope may be referred to as a radiopharmaceutical. References herein to a compound of formula (1) that is "conjugated" to a radioisotope refer to compounds in which the radioisotope is R M or conjugated to a compound of formula (1). M Examples of compounds of formula (1) conjugated to radioisotopes via: [ka]

[0178] PSMA-targeting ligands In the above formula (1), A is a PSMA targeting ligand. In one embodiment, A is a urea component (A-1): [ka] (In the formula, [ka] represents the bond attaching A to the remainder of the molecule of formula (1).

[0179] In some embodiments, R 21 is uninterrupted or interrupted, optionally replaced -C 1~20 In some embodiments, R 21 is uninterrupted or interrupted, optionally replaced -C 1~10 In some embodiments, R 21 is uninterrupted or interrupted, optionally replaced -C 1~6 In some embodiments, R 21 is one or more R 8 is optionally replaced by R 21 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0180] In some embodiments, each R 22 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted. 22 is H. In some embodiments, each R 22 is one or more R 8 is optionally replaced by R 22One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0181] In some embodiments, Z 1 ~Z 3 are each independently -C(=O)OR 9 , -S(=O)OR 9 , -S(=O)2OR 9 , -S(=O)(OR 9 )2, -OS(=O)OR 9 , -OS(=O)2OR 9 , -OS(=O)(OR 9 )2, -P(=O)(OR 9 )2, -P(=O)OR 9 (R 9 ), -OP(=O)(OR 9 )2, and -OP(=O)OR 9 (R 9 In one embodiment, Z 1 ~Z 3 are each independently -C(=O)OR 9 In one embodiment, Z 1 ~Z 3 are each -COOH.

[0182] In some embodiments, A is a group represented by formula (A-2): [ka] (In the formula, [ka] represents the bond attaching A to the rest of the molecule of formula (1); R 21 is one or more R 8 C optionally replaced with 1~20 A PSMA-targeting ligand having the structure:

[0183] R 8 ~R 11 In the above formula (1), R 1 ~R 7 , R 12 ~R 14 , and R 19 ~R 24 Each of may be optionally substituted. In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 , R 13 , R 14 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 Each of the 8 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 , R 13 , R 14 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 One or more R 8 It will be understood that when a group is not substituted with a hydrogen atom, the hydrogen atom remains as a substitute.

[0184] In some embodiments, R 1 is one, two, three, four, five or more R 8 In one embodiment, R 1 is one R 8 In one embodiment, R 1 are two R 8 In one embodiment, R 1 The three R's 8In one embodiment, R 1 The four R's 8 In one embodiment, R 1 The Five R's 8 In one embodiment, R 1 is more than 5 R 8 It is substituted with a substituent.

[0185] In some embodiments, R 2 is one, two, three, four, five or more R 8 In one embodiment, R 2 is one R 8 In one embodiment, R 2 are two R 8 In one embodiment, R 2 The three R's 8 In one embodiment, R 2 The four R's 8 In one embodiment, R 2 The Five R's 8 In one embodiment, R 2 is more than 5 R 8 It is substituted with a substituent.

[0186] In some embodiments, R 3 is one, two, three, four, five or more R 8 In one embodiment, R 3 is one R 8 In one embodiment, R 3 are two R 8 In one embodiment, R 3 The three R's 8 In one embodiment, R 3 The four R's 8 In one embodiment, R 3 The Five R's8 In one embodiment, R 3 is more than 5 R 8 It is substituted with a substituent.

[0187] In some embodiments, R 4 is one, two, three, four, five or more R 8 In one embodiment, R 4 is one R 8 In one embodiment, R 4 are two R 8 In one embodiment, R 4 The three R's 8 In one embodiment, R 4 The four R's 8 In one embodiment, R 4 The Five R's 8 In one embodiment, R 4 is more than 5 R 8 It is substituted with a substituent.

[0188] In some embodiments, R 5 is one, two, three, four, five or more R 8 In one embodiment, R 5 is one R 8 In one embodiment, R 5 are two R 8 In one embodiment, R 5 The three R's 8 In one embodiment, R 5 The four R's 8 In one embodiment, R 5 The Five R's 8 In one embodiment, R 5 is more than 5 R 8 It is substituted with a substituent.

[0189] In some embodiments, R 6 is one, two, three, four, five or more R 8 In one embodiment, R 6 is one R 8 In one embodiment, R 6 are two R 8 In one embodiment, R 6 The three R's 8 In one embodiment, R 6 The four R's 8 In one embodiment, R 6 The Five R's 8 In one embodiment, R 6 is more than 5 R 8 It is substituted with a substituent.

[0190] In some embodiments, R 7 is one, two, three, four, five or more R 8 In one embodiment, R 7 is one R 8 In one embodiment, R 7 are two R 8 In one embodiment, R 7 The three R's 8 In one embodiment, R 7 The four R's 8 In one embodiment, R 7 The Five R's 8 In one embodiment, R 7 is more than 5 R 8 It is substituted with a substituent.

[0191] In some embodiments, R 12 is one, two, three, four, five or more R 8In one embodiment, R 12 is one R 8 In one embodiment, R 12 are two R 8 In one embodiment, R 12 The three R's 8 In one embodiment, R 12 The four R's 8 In one embodiment, R 12 The Five R's 8 In one embodiment, R 12 is more than 5 R 8 It is substituted with a substituent.

[0192] In some embodiments, R 13 is one, two, three, four, five or more R 8 In one embodiment, R 13 is one R 8 In one embodiment, R 13 are two R 8 In one embodiment, R 14 The three R's 8 In one embodiment, R 13 The four R's 8 In one embodiment, R 13 The Five R's 8 In one embodiment, R 13 is more than 5 R 8 It is substituted with a substituent.

[0193] In some embodiments, R 14 is one, two, three, four, five or more R 8 In one embodiment, R 14 is one R 8 In one embodiment, R 14 are two R8 In one embodiment, R 14 The three R's 8 In one embodiment, R 14 The four R's 8 In one embodiment, R 14 The Five R's 8 In one embodiment, R 14 is more than 5 R 8 It is substituted with a substituent.

[0194] In some embodiments, R 19 is one, two, three, four, five or more R 8 In one embodiment, R 19 is one R 8 In one embodiment, R 19 are two R 8 In one embodiment, R 19 The three R's 8 In one embodiment, R 19 The four R's 8 In one embodiment, R 19 The Five R's 8 In one embodiment, R 19 is more than 5 R 8 It is substituted with a substituent.

[0195] In some embodiments, R 20 is one, two, three, four, five or more R 8 In one embodiment, R 20 is one R 8 In one embodiment, R 20 are two R 8 In one embodiment, R 20 The three R's 8 In one embodiment, R 20The four R's 8 In one embodiment, R 20 The Five R's 8 In one embodiment, R 20 is more than 5 R 8 It is substituted with a substituent.

[0196] In some embodiments, R 21 is one, two, three, four, five or more R 8 In one embodiment, R 21 is one R 8 In one embodiment, R 21 are two R 8 In one embodiment, R 21 The three R's 8 In one embodiment, R 21 The four R's 8 In one embodiment, R 21 The Five R's 8 In one embodiment, R 21 is more than 5 R 8 It is substituted with a substituent.

[0197] In some embodiments, R 22 is one, two, three, four, five or more R 8 In one embodiment, R 22 is one R 8 In one embodiment, R 22 are two R 8 In one embodiment, R 22 The three R's 8 In one embodiment, R 22 The four R's 8 In one embodiment, R 22 The Five R's 8 In one embodiment, R22 is more than 5 R 8 It is substituted with a substituent.

[0198] In some embodiments, R 23 is one, two, three, four, five or more R 8 In one embodiment, R 23 is one R 8 In one embodiment, R 23 are two R 8 In one embodiment, R 23 The three R's 8 In one embodiment, R 23 The four R's 8 In one embodiment, R 23 The Five R's 8 In one embodiment, R 23 is more than 5 R 8 It is substituted with a substituent.

[0199] In some embodiments, R 24 is one, two, three, four, five or more R 8 In one embodiment, R 24 is one R 8 In one embodiment, R 24 are two R 8 In one embodiment, R 24 The three R's 8 In one embodiment, R 24 The four R's 8 In one embodiment, R 24 The Five R's 8 In one embodiment, R 24 is more than 5 R 8 It is substituted with a substituent.

[0200] R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 , R 13 , R 14 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 One or more of the R 8 When substituted with substituents, the one or more substituents may be the same or different (e.g., R 8 It will be understood that the substituents are selected independently of each other.

[0201] In the above formula (1), Y 1 ~Y 4 Each of Y may be optionally substituted. 1 , Y 2 , Y 3 , and Y 4 Each of the 8 Y 1 , Y 2 , Y 3 , and Y 4 One or more R 8 It will be understood that if Y is not substituted, a hydrogen atom remains as a substitution. 1 is one, two, three, four, five or more R 8 In one embodiment, Y is substituted with a substituent. 1 is one R 8 In one embodiment, Y is substituted with a substituent. 1 are two R 8 In one embodiment, Y is substituted with a substituent. 1 The three R's 8 In one embodiment, Y is substituted with a substituent. 1 The four R's 8 In one embodiment, Y is substituted with a substituent. 1 The Five R's8 In one embodiment, Y is substituted with a substituent. 1 is more than 5 R 8 In one embodiment, Y is substituted with a substituent. 2 is one R 8 In one embodiment, Y is substituted with a substituent. 2 are two R 8 In one embodiment, Y is substituted with a substituent. 2 The three R's 8 In one embodiment, Y is substituted with a substituent. 2 The four R's 8 In one embodiment, Y is substituted with a substituent. 2 The Five R's 8 In one embodiment, Y is substituted with a substituent. 2 is more than 5 R 8 In one embodiment, Y is substituted with a substituent. 3 is one R 8 In one embodiment, Y is substituted with a substituent. 3 are two R 8 In one embodiment, Y is substituted with a substituent. 3 The three R's 8 In one embodiment, Y is substituted with a substituent. 3 The four R's 8 In one embodiment, Y is substituted with a substituent. 3 The Five R's 8 In one embodiment, Y is substituted with a substituent. 3 is more than 5 R 8 In one embodiment, Y is substituted with a substituent. 4 is one R 8 In one embodiment, Y is substituted with a substituent. 4 are two R 8 In one embodiment, Y is substituted with a substituent. 4 The three R's 8 In one embodiment, Y is substituted with a substituent. 4 The four R's 8 In one embodiment, Y is substituted with a substituent. 4 The Five R's8 In one embodiment, Y is substituted with a substituent. 4 is more than 5 R 8 It is substituted with a substituent.

[0202] In the above formula (1), each L 1 , L 2 and L 3 is optionally substituted. In one embodiment, each L 1 , L 2 and L 3 is one or more R 8 L 1 , L 2 and L 3 One or more R 8 It will be understood that when L is not substituted with 1 is one, two, three, four, five or more R 8 In one embodiment, L 1 is one R 8 In one embodiment, L 1 are two R 8 In one embodiment, L 1 The three R's 8 In one embodiment, L 1 The four R's 8 In one embodiment, L 1 The Five R's 8 In one embodiment, L 1 is more than 5 R 8 In one embodiment, L 2 is one R 8 In one embodiment, L 2 are two R 8 In one embodiment, L 2 The three R's 8 In one embodiment, L 2 The four R's8 In one embodiment, L 2 The Five R's 8 In one embodiment, L 2 is more than 5 R 8 In one embodiment, L 3 is one R 8 In one embodiment, L 3 are two R 8 In one embodiment, L 3 The three R's 8 In one embodiment, L 3 The four R's 8 In one embodiment, L 3 The Five R's 8 In one embodiment, L 3 is more than 5 R 8 It is substituted with a substituent.

[0203] In the above formula (1), each R 8 are independently H, halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -NO2, -CN, -SCN, -N3, =O, -N(R 9 )2, -C(=O)N(R 9 )2, -S(=O)N(R 9 )2, -S(=O)2N(R 9 )2, -OR 9 , -SR 9 , -OC(=O)R 9 , -C(=O)R 9, -C(=O)OR 9 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)OR 9 , -S(=O)2OR 9 , -S(=O)(OR 9 )2, -OS(=O)R 9 , -OS(=O)2R 9 , -OS(=O)OR9, -OS(=O)2OR 9 , -OS(=O)(OR 9 )2, -N(R 9 )C(=O)R 9 , -N(R 9 )S(=O)R 9 , -N(R 9 )C(=O)N(R 9 )2, -N(R 9 )S(=O)2R 9 , -P(=O)(OR 9 )2, -P(=O)OR 9 (R 9 ), -P(=O)(R 9 )2, -OP(=O)(OR 9 )2, -OP(=O)OR 9 (R 9 ) and -OP(=O)(R 9 )2.

[0204] In the above formula (1), R 8 But C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 When alkyl-3 to 10-membered heterocyclyl, each C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 In some embodiments, R 8 But C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 When alkyl-3 to 10-membered heterocyclyl, each C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may have one, two, three, four, five, or more than five R 10 R may be optionally substituted with a substituent. 8 One or more R 10 When substituted with substituents, the one or more substituents may be the same or different (e.g., R 10 It will be understood that the substituents are selected independently of each other.

[0205] In the above formula (1), each R 9 are independently H, C 1~6 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~6 Alkyl-3 to 10-membered carbocyclyl, and C 1~6 It may be selected from the group consisting of alkyl-3 to 10 membered heterocyclyl.

[0206] In the above formula (1), R 9 But C 1~6 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~6 Alkyl-3 to 10-membered carbocyclyl, and C1~6 When alkyl-3 to 10-membered heterocyclyl, each C 1~6 Alkyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be one or more R 10 In some embodiments, R 9 But C 1~6 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~6 Alkyl-3 to 10-membered carbocyclyl, and C 1~6 When alkyl-3 to 10-membered heterocyclyl, each C 1~6 Alkyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may have 1, 2, 3, 4, 5, or more than 5 R 10 R may be optionally substituted with a substituent. 9 One or more R 10 When substituted with substituents, the one or more substituents may be the same or different (e.g., R 10 It will be understood that the substituents are selected independently of each other.

[0207] In the above formula (1), each R 10 are independently H, halogen, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -C(=O)N(R 11 )2, -N(R 11 )C(=O)R 11 , -OR 11 , -P(=O)(OR 11 )2, -P(=O)OR 11 (R 11 ), -P(=O)(R 11 )2, C 1~6 Alkyl and -OC 1~6 In the above formula (1), each R 11 are independently H, C 1~10 Alkyl, C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 In one embodiment, each R 11 are independently H and C 1~6 In one embodiment, R 11 is H. In one embodiment, R 11 is C 1~6 It is alkyl.

[0208] In the above formula (1), each R 1 and R 2 are independently halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C may be optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, each R 1 and R 2 are independently halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R 1 and R 2 are independently halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 It may be optionally substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH. In some embodiments, R 1 and R 2 may be optionally substituted with one or more groups independently selected from halogen, —NO 2 , —NH 2 , —CN, —SCN, —COOH, and —OH.

[0209] In one embodiment, R 1 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C is optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10In some embodiments, R 1 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R 1 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 Optionally substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH. In some embodiments, R 1 is optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 1 is unsubstituted (i.e., substituted with H).

[0210] In one embodiment, R 1 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C is an aryl or alkylaryl optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, R 1 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R is an aryl or alkylaryl optionally substituted with one or more groups selected from 1 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 In some embodiments, R is an aryl or alkylaryl optionally substituted with one or more groups selected from haloalkyl, —NO, —NH, —CN, —SCN, —COOH, and —OH. 1 is benzyl optionally substituted with one or more groups selected from halogen, —NO 2 , —NH 2 , —CN, —SCN, —COOH, and —OH. In some embodiments, R 1is aryl or alkylaryl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 1 is unsubstituted aryl or unsubstituted alkylaryl (ie, "substituted" with H).

[0211] In one embodiment, R 1 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C is phenyl or benzyl optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, R 1 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11, and -OR 11 In some embodiments, R is phenyl or benzyl optionally substituted with one or more groups selected from 1 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 In some embodiments, R is phenyl or benzyl optionally substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH. 1 is phenyl or benzyl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In some embodiments, R 1 is phenyl or benzyl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 1 is unsubstituted phenyl or unsubstituted benzyl (i.e., "substituted" with H).

[0212] In one embodiment, R 1 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 benzyl optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10Alkynyl is a group consisting of one or more R 10 In some embodiments, R 1 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R is benzyl optionally substituted with one or more groups selected from 1 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 benzyl optionally substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH. In some embodiments, R 1 is benzyl optionally substituted with one or more groups selected from halogen, —NO 2 , —NH 2 , —CN, —SCN, —COOH, and —OH. In some embodiments, R 1 is benzyl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 1 is unsubstituted benzyl (i.e., "substituted" with H).

[0213] In one embodiment, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C is optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R 2 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 Optionally substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH. In some embodiments, R 2is optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 2 is optionally substituted with one or more halogens (eg, one or more of I, Br, Cl, or Br) or —OH.

[0214] In one embodiment, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C is an aryl or alkylaryl optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11, and -OR 11 In some embodiments, R is an aryl or alkylaryl optionally substituted with one or more groups selected from 2 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 In some embodiments, R is an aryl or alkylaryl optionally substituted with one or more groups selected from haloalkyl, —NO, —NH, —CN, —SCN, —COOH, and —OH. 2 is aryl or alkylaryl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 2 is aryl or alkylaryl optionally substituted with one or more halogen (eg, one or more of I, Br, Cl, or Br) or —OH.

[0215] In one embodiment, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C is phenyl or benzyl optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10In some embodiments, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R is phenyl or benzyl optionally substituted with one or more groups selected from 2 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 In some embodiments, R is phenyl or benzyl optionally substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH. 2 is phenyl or benzyl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In some embodiments, R 2 is phenyl or benzyl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 2 is phenyl or benzyl optionally substituted with one or more halogens (eg, one or more of I, Br, Cl, or Br) or —OH.

[0216] In one embodiment, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 benzyl optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R is benzyl optionally substituted with one or more groups selected from 2 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 benzyl optionally substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH. In some embodiments, R 2is benzyl optionally substituted with one or more groups selected from halogen, —NO 2 , —NH 2 , —CN, —SCN, —COOH, and —OH. In some embodiments, R 2 is benzyl optionally substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 2 is benzyl optionally substituted with one or more halogens (eg, one or more of I, Br, Cl, or Br) or —OH.

[0217] In one embodiment, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C is an aryl or alkylaryl substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R is an aryl or alkylaryl substituted with one or more groups selected from 2 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 In some embodiments, R is an aryl or alkylaryl substituted with one or more groups selected from haloalkyl, —NO, —NH, —CN, —SCN, —COOH, and —OH. 2 is aryl or alkylaryl substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 2 is aryl or alkylaryl substituted with one or more halogens (eg, one or more of I, Br, Cl, or Br) or —OH.

[0218] In one embodiment, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C is phenyl or benzyl substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R is phenyl or benzyl substituted with one or more groups selected from 2 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 In some embodiments, R is phenyl or benzyl substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH. 2 is phenyl or benzyl substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In some embodiments, R 2 is phenyl or benzyl substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 2 is phenyl or benzyl substituted with one or more halogens (eg, one or more of I, Br, Cl, or Br) or —OH.

[0219] In one embodiment, R 2 is a halogen, C 1~10Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 benzyl substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 In some embodiments, R 2 is a halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 In some embodiments, R is benzyl substituted with one or more groups selected from 2 is a halogen, C 1~6 Alkyl, OC 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 In some embodiments, R is benzyl substituted with one or more groups selected from haloalkyl, -NO, -NH, -CN, -SCN, -COOH, and -OH.2 is benzyl substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In some embodiments, R 2 is benzyl substituted with one or more groups selected from halogen, —NO, —NH, —CN, —SCN, —COOH, and —OH. In one embodiment, R 2 is benzyl substituted with one or more halogens (eg, one or more of I, Br, Cl, or Br) or —OH.

[0220] In one embodiment, R 1 is the expression: [ka] is the basis of R 2 is the expression: [ka] is a group of the formula [ka] is R 1 and R 2 each represents a bond attaching the group to the remainder of the compound of formula (1).

[0221] In one embodiment, R 1 is the expression: [ka] R 2 is the expression: [ka] is a group of the formula [ka] is R 1 and R 2 each represents a bond attaching the group to the remainder of the compound of formula (1).

[0222] In the above formula (1), each R 3 independently one or more groups H, C 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 and each C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 In some embodiments, R 3 Each of the 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, -C(=O)OC 1~6 In one embodiment, R 3 is unsubstituted (i.e., substituted with H).

[0223] In the above formula (1), R 4 ~R 7 are each independently C 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 and each C may be optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 In one embodiment, R 4 ~R 7 is unsubstituted (i.e., substituted with H).

[0224] In the above formula (1), R 12 and R 13 are each independently C 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 and each C may be optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 In one embodiment, R 12 and R 13 is unsubstituted (i.e., substituted with H).

[0225] In the above formula (1), each R 14 are independently halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 9 , -C(=O)OR 9 , -N(R 9 )C(=O)R 9 , and -OR 9 and each C may be optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl and C 2~10 Alkynyl is a group consisting of one or more R 10 is optionally replaced by

[0226] In the above formula (1), R 19 ~R 24 are each independently C 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 and each C may be optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 In some embodiments, R 19 and R 24 Each of the 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, -C(=O)OC 1~6 In one embodiment, R 19 and R 24 is unsubstituted (i.e., substituted with H).

[0227] In the above formula (1), L 1 , L 2 and L 3 Each of the groups independently represents R 8 In some embodiments, L 1 , L 2 and L 3 Each of the 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 and each C may be optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 In some embodiments, L1 , L 2 and L 3 Each of the 1~10 Alkyl, OC 1~10 Alkyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 In some embodiments, L 1 , L 2 and L 3 Each of the 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, -C(=O)OC 1~6 In one embodiment, L is optionally substituted with one or more groups selected from alkyl. 1 , L 2 and L 3 Each of L may independently be optionally substituted with one or more -NH, -OH, or -COOH. 1 , L 2 and L 3 Each of may independently be optionally substituted with one or more -COOH.

[0228] In the above formula (1), L 1 , L 2 and L 3 Each of the groups is independently R 8 In some embodiments, L 1 , L 2 and L 3 Each of the 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10Alkyl-3 to 10-membered heterocyclyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 and each C may be optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 In some embodiments, L 1 and L 2 are each independently C 1~10 Alkyl, OC 1~10 Alkyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 In some embodiments, L 1 and L 2 are each independently C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, -C(=O)OC 1~6 In one embodiment, L is optionally substituted with one or more groups selected from alkyl. 1 , L 2 and L 3 Each of L may independently be optionally substituted with one or more -NH, -OH, or -COOH. 1 and L 2 may each be optionally substituted with one or more -COOH.

[0229] In one embodiment, L 1 is uninterrupted or interrupted by one or more groups selected from -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH; C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 -C optionally substituted with one or more groups selected from alkyl 1~20 In one embodiment, L 1 is one or more -C(=O)NR 3 -(e.g., -C(=O)NH-) -C interrupted by an amide bond 1~20 alkyl, C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, -C(=O)OC 1~6 In one embodiment, L is optionally substituted with one or more groups selected from alkyl. 1 is one or more -C(=O)NR 3 -(e.g., -C(=O)NH-) -C interrupted by an amide bond 1~20 alkyl, optionally substituted with one or more groups selected from -NH, -OH, or -COOH. 1 is one or more -C(=O)NR 3 -(e.g., -C(=O)NH-) -C interrupted by an amide bond 1~20 alkyl, optionally substituted with one or more -COOH.

[0230] In one embodiment, L 2 is uninterrupted or interrupted by one or more groups selected from -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH; C 1~10 Alkyl, OC 1~10Alkyl, -NH2, -OH, -COOH, and -C(=O)OC 1~6 -C optionally substituted with one or more groups selected from alkyl 1~20 In one embodiment, L 2 is C 1~10 Alkyl, OC 1~10 Alkyl, -NH2, -OH, -COOH, -C(=O)OC 1~6 C optionally substituted with one or more groups selected from alkyl 1~20 In one embodiment, L 2 is optionally substituted with one or more groups selected from -NH, -OH, or -COOH; 1~20 In one embodiment, L 2 is optionally substituted with one or more -COOH 1~20 It is alkyl-.

[0231] In one embodiment, L 3 is uninterrupted or interrupted by one or more groups selected from O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH; C 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -N(R 9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 -C optionally substituted with one or more groups selected from 1~20 Alkyl- or -C 1~10 alkyl-, and each C 1~10 Alkyl, C 1~10 Haloalkyl, C2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be substituted by one or more R 10 is optionally replaced by

[0232] Compound of formula (1) In some embodiments, the compound of formula (1) has the following formulae (1C) to (1H): [ka] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n, L 1 , L 2 , X 1 , X 2 , X 3 , R 1 , R 2 , R 21 and R M is as described herein.

[0233] In some embodiments, the compound of formula (1) has the following formulae (1I) to (1K): [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, In the formula, n, L 1 , L 2 , X 1 , X 2 , X 3 , R 1 , R 2 , R 21 and R M is as described herein.

[0234] In some embodiments, the compound of formula (1) has the formula (1L): [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, In the formula, n, L 2 , X 3 , R 1 , and R 2 is as described herein.

[0235] In one embodiment, the compound of formula (1) is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0236] In some embodiments, the compound of formula (1) is [ka] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0237] In some embodiments, the compound of formula (1) is HO-Glu-CO-Lys[SubA-D-Lys-D-Phe-D-Tyr(3I)-(Pent- 212 Pb-DO3AM)]-OH (chemical name 3S,7S,26S,29R,32R)-29-benzyl-32-(4-hydroxy-3-iodobenzyl)-5,13,20,28,31,34-hexaoxo-37-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,21,27,30,33-heptaazaheptatriacontane-1,3,7,26,37-pentacarboxylic acid), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0238] In some embodiments, the compound of formula (1) is [ka] or a salt, solvate or stereoisomer thereof.

[0239] In some embodiments, the compound of formula (1) is [ka] or a salt, solvate or stereoisomer thereof.

[0240] composition While the compound of Formula (1) or a pharmaceutically acceptable salt, solvate, or enantiomer thereof may be administered alone to a patient in need thereof in some embodiments, it is more typically administered as part of a pharmaceutical composition or formulation. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, and a pharmaceutically acceptable excipient. Pharmaceutical compositions include one or more pharmaceutically acceptable diluents, carriers, or excipients (collectively referred to herein as "excipient" materials).

[0241] The present disclosure also provides pharmaceutical compositions for both veterinary and human medical use comprising a compound of formula (1) or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, together with one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients, stabilizers, or the like. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.

[0242] Examples of pharmaceutical compositions include those suitable for parenteral administration, including subcutaneous, intradermal, intramuscular, intravenous, and intraarticular administration. Other, less preferred, examples of pharmaceutical compositions include those suitable for oral, inhalation, rectal, intraperitoneal, and topical administration.

[0243] In some embodiments, the pharmaceutical composition contains a radioisotope (e.g., 212Pb). In some embodiments, the amount of radioisotope in the composition (in MBq) is at least about 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 600, 800, or 1000. In some embodiments, the amount of radioisotope in the composition (in MBq) is less than about 1000, 800, 600, 500, 400, 300, 200, 150, 120, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 1, or 0.1 MBq of radioisotope to a patient. The amount of radiopharmaceutical may be in the range provided by any two of these upper and / or lower limits, for example, from about 10 MBq to about 500 MBq.

[0244] In some embodiments, a diagnostic composition is provided comprising a compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, and a pharmaceutically acceptable carrier.

[0245] Therapeutic and Diagnostic Methods and Uses Surprisingly, radioactive isotopes ( 212 Pb) demonstrates high uptake in PSMA-expressing tumor tissues with reduced retention in the kidney after intravenous injection, and in some embodiments, 212 Pb]-PSMA-I&T have been found to exhibit a much higher post-injection tumor-to-kidney ratio compared to [Pb]-PSMA-I&T.

[0246] Accordingly, there is provided a compound of formula (1) as described herein for use in the diagnosis, treatment and / or prevention of PSMA-expressing cancer.

[0247] In some embodiments, a pharmaceutical composition is provided comprising a compound of Formula (1) described herein and a pharmaceutically acceptable excipient.

[0248] In another embodiment, there is provided a method for treating and / or preventing a PSMA-expressing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (1) as described herein, or a pharmaceutical composition as described herein.

[0249] In another embodiment, there is provided a use of a compound of Formula (1) as described herein or a pharmaceutical composition as described herein for treating and / or preventing a PSMA-expressing cancer.

[0250] In another embodiment, there is provided a use of a compound of Formula (1) as described herein or a pharmaceutical composition as described herein in the manufacture of a medicament for treating and / or preventing a PSMA-expressing cancer.

[0251] In one embodiment, the PSMA-expressing cancer is selected from the group consisting of prostate cancer, conventional renal cell carcinoma, transitional cell carcinoma of the bladder, testicular germ cell carcinoma, neuroendocrine cancer, colorectal cancer, brain tumor, and breast cancer. In a particularly preferred embodiment, the PSMA-expressing cancer is prostate cancer or breast cancer, particularly prostate cancer. In one embodiment, the PSMA-expressing cancer may be metastatic castration-resistant prostate cancer (mCRPC).

[0252] The amount of a compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, required to achieve a therapeutic effect will, of course, vary depending on the particular compound, the radioisotope conjugated thereto, the route of administration, the subject being treated, including the type, species, age, weight, sex, and condition of the subject being treated, the subject's renal and hepatic function, and the particular condition, disorder, or disease being treated, and its severity. A skilled artisan or clinician can readily determine and prescribe the effective amount of drug required to prevent or treat the condition, disorder, or disease.

[0253] When used for the indicated effects, the dosage of the compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, may range, for example, from about 0.01 mg per kilogram of body weight per day (mg / kg / day) to about 1000 mg / kg / day. In one embodiment, the dosage of the compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, is about 0.01 to 1000, 0.1 to 500, 0.1 to 100, or 1 to 50 mg / kg / day. In one embodiment, the dosage of the compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, is about 0.01 to 1000 mg / kg / day. In one embodiment, the dosage of the compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, is about 0.1 to 100 mg / kg / day. In one embodiment, the dosage of the compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, is greater than about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, or 1000 mg / kg / day. In one embodiment, the dosage of the compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, is greater than about 0.01 mg / kg / day. In one embodiment, the dosage of the compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, is less than about 5000, 1000, 75, 50, 20, 10, 1, or 0.1 mg / kg / day. In one embodiment, the dosage of the compound of Formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, is less than about 1000 mg / kg / day.

[0254] The compound of formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, may be administered, for example, as a single daily dose, or the total daily dosage may be administered in divided doses two, three, or four times daily. In one embodiment, the compound of formula (1), or a pharmaceutically acceptable salt, solvate, or enantiomer thereof, may be administered less frequently than once daily, for example, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. When administered intravenously, for example, an infusion of the compound of formula (1) over a period of time may be used, and may include dose escalation.

[0255] In one embodiment, a radioisotope (e.g., 212 Pb) is administered to a patient in need thereof (e.g., via intravenous injection) in an amount effective to prevent and / or treat prostate cancer. In one embodiment, the radioactive isotope (e.g., 212 A radiopharmaceutical comprising a compound of Formula (1) complexed to Pb is administered to a patient in need thereof in an amount effective to deliver about 0.1 MBq to about 1000 MBq of the radioisotope to the patient. In one embodiment, the radioisotope (e.g., 212 Pb), is administered to a patient in need thereof in an amount effective to deliver at least about 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 600, 800, or 1000 MBq of the radioisotope to the patient. In one embodiment, the radioisotope (e.g., 212A radiopharmaceutical comprising a compound of Formula (1) complexed to Pb is administered to a patient in need thereof in an amount effective to deliver less than about 1000, 800, 600, 500, 400, 300, 200, 150, 120, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 1, or 0.1 MBq of the radioisotope to the patient. The amount of the radiopharmaceutical administered to the patient can be within a range provided by any two of these upper and / or lower limits, e.g., from about 10 MBq to about 500 MBq of the radioisotope per patient.

[0256] In some embodiments, radioisotopes (e.g., 212 A patient receiving a radiopharmaceutical comprising a compound of Formula (1) complexed to a radioisotope (Pb) may remain radioactive (e.g., have a radioisotope level at or above the threshold considered radioactive by a physician) for about 1 hour to about 96 hours after administration. In some embodiments, a patient receiving a radiopharmaceutical comprising a compound of Formula (1) complexed to a radioisotope may remain radioactive for at least about 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, or 120 hours after administration. In some embodiments, a patient receiving a radiopharmaceutical comprising a compound of Formula (1) complexed to a radioisotope may remain radioactive for at least about 120, 96, 72, 48, 24, 12, 10, 8, 6, 5, 4, 3, 2, or 1 hour after administration. The patient may remain radioactive for a period within the range provided by any two of these upper and / or lower limits, for example, between about 1 and 24 hours, or about 1 and 12 hours.

[0257] In some embodiments, radioisotopes (e.g., 212The PSMA-expressing tumor uptake (in %ID / g at 24 hours post injection) following administration of a radiopharmaceutical comprising a compound of Formula (1) conjugated to a radioisotope (Pb) can be at least about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, or 50. In some embodiments, the PSMA-expressing tumor uptake (in %ID / g at 24 hours post injection) following administration of a radiopharmaceutical comprising a compound of Formula (1) conjugated to a radioisotope can be less than about 50, 20, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.1. The %ID / g uptake of the radiopharmaceutical can be in a range provided by any two of these upper and / or lower limits, e.g., from about 1 to about 20 %ID / g at 24 hours post injection.

[0258] In some embodiments, radioisotopes (e.g., 212 The renal clearance (in %ID / g 24 hours after injection) following administration of a radiopharmaceutical comprising a compound of Formula (1) complexed to Pb can be less than about 20, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.01, or 0.001. The %ID / g renal clearance of the radiopharmaceutical can be within a range provided by any two of these upper and / or lower limits, e.g., from about 0.01 to about 5%ID / g 24 hours after injection.

[0259] In some embodiments, the compound of formula (1) may be conjugated to a radioisotope suitable for use as an imaging agent. For example, the compound of formula (1) may be 68 Ga, 64 Cu, 55 Co or 89 It may be conjugated to a positron-emitting radioisotope such as Zr to provide an imaging agent that can be used as a positron emission tomography (PET) imaging agent. Alternatively, the compound of formula (1) 203 It may be conjugated to a gamma-emitting radioisotope such as Pb to provide an imaging agent that can be used as a single photon emission computed tomography (SPECT) imaging agent.

[0260] In one embodiment, there is provided an imaging agent comprising a compound of formula (1) described herein. M is conjugated to a radioisotope. M is conjugated to a positron-emitting radioisotope, thus providing a positron emission tomography (PET) imaging agent. In one embodiment, the compound is conjugated to a radioisotope. In one embodiment, the compound is conjugated to a positron-emitting radioisotope, thus providing a positron emission tomography (PET) imaging agent.

[0261] As used herein, a "positron-emitting radioisotope" is a radioisotope that is neutron-deficient and emits positrons (β+) and electron neutrinos. [ka] positron-emitting radioisotopes refer to radioisotopes that achieve stability through the nuclear transmutation of protons into neutrons, resulting in the emission of a positron. The positron then combines with a nearby electron, simultaneously emitting two distinguishable gamma rays in opposite directions. These are detected by a PET scanner / multi-head gamma camera, which can pinpoint their origin with great precision. In one embodiment, the positron-emitting radioisotope is 68 Ga, 64 Cu, 55 Co, and 89 Zr is selected from the group consisting of

[0262] As used herein, "gamma-emitting radioisotope" refers to a radioisotope that emits gamma rays, which can be measured directly, in contrast to positron-emitting radioisotopes, which emit a positron that annihilates with a nearby electron, resulting in the emission of two gamma photons in opposite directions for detection by a gamma camera.

[0263] In one embodiment, a diagnostic composition is also provided that includes an imaging agent described herein and a pharmaceutically acceptable excipient.

[0264] In one embodiment, there is provided a method of imaging tissue in a subject, the method comprising administering to the subject a diagnostically effective amount of a compound of Formula (1), imaging agent, or diagnostic composition described herein.

[0265] In another embodiment, there is provided a use of a compound of Formula (1), imaging agent, or diagnostic composition described herein for imaging a tissue in a subject. In another embodiment, there is provided a use of a compound of Formula (1), imaging agent, or diagnostic composition described herein in the manufacture of an imaging agent for imaging a tissue in a subject.

[0266] In another embodiment, there is provided an ex vivo method of imaging a tissue sample comprising a diagnostically effective amount of a compound of Formula (1), imaging agent, or diagnostic composition described herein.

[0267] Imaging can be performed in the usual manner, for example, by injecting an imaging composition in an amount sufficient to provide adequate imaging, followed by scanning with a suitable imaging or scanning instrument, such as a tomographic or gamma camera. In certain embodiments, a method of imaging a region in a patient includes (i) administering to the subject a diagnostically effective amount of an imaging agent and exposing the region of the subject to a scanning device, and (ii) obtaining an image of the region of the subject.

[0268] In some embodiments, the tissue imaged is a PSMA-expressing tumor tissue. In one embodiment, the PSMA-expressing tumor tissue is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC).

[0269] In one embodiment, there is provided a positron emission tomography (PET) imaging method comprising a compound of formula (1) described herein, wherein R M Alternatively, the compound of formula (1) may be ionized with a positron-emitting radioisotope, e.g. 68 Ga, 64 Cu, 55 Co, or 89 It is complexed with Zr.

[0270] In some embodiments, a method of imaging tissue in a subject, such as a PSMA-expressing tumor tissue, is provided, comprising: subjecting the tissue to a positron-emitting radioisotope, e.g., 68 Ga, 64 Cu, 55 Co, or 89 with a PET imaging agent comprising a compound of formula (1) described herein complexed to Zr.

[0271] In some embodiments, a method of imaging tissue in a subject, such as a PSMA-expressing tumor tissue, is provided, comprising: subjecting the tissue to a positron-emitting radioisotope, e.g., 68 Ga, 64 Cu, 55 Co, or 89 with a PET imaging agent comprising a compound of formula (1) described herein complexed to Zr.

[0272] In another embodiment, a positron-emitting radioisotope, e.g., 68 Ga, 64 Cu, 55 Co, or 89 There is provided the use of a PET imaging agent comprising a compound of formula (1) as described herein complexed to Zr.

[0273] In another embodiment, in the manufacture of a PET imaging agent for imaging tissue in a subject, a positron-emitting radioisotope, e.g., 68 Ga, 64 Cu, 55 Co, or 89 There is provided the use of a PET imaging agent comprising a compound of formula (1) as described herein complexed to Zr.

[0274] In one embodiment, there is provided a single photon emission computed tomography (SPECT) imaging agent comprising a compound of formula (1) as described herein, wherein R M is a gamma-emitting radioisotope, e.g., 203In one embodiment, there is provided a single photon emission computed tomography (SPECT) imaging agent comprising a compound of formula (1) described herein, wherein the compound of formula (1) is complexed with a gamma-emitting radioisotope, e.g., 203 It is complexed with Pb.

[0275] In some embodiments, a method of imaging tissue in a subject, such as a PSMA-expressing tumor tissue, is provided, comprising: subjecting the tissue to a gamma-emitting radioisotope, e.g., 203 with a SPECT imaging agent comprising a compound of formula (1) described herein complexed to Pb.

[0276] In some embodiments, a method of imaging tissue in a subject, such as a PSMA-expressing tumor tissue, is provided, comprising: subjecting the tissue to a gamma-emitting radioisotope, e.g., 203 with a SPECT imaging agent comprising a compound of formula (1) described herein complexed to Pb.

[0277] In another embodiment, gamma-emitting radioisotopes, e.g., 203 There is provided the use of a SPECT imaging agent comprising a compound of formula (1) as described herein complexed to Pb.

[0278] In another embodiment, in the manufacture of a PET imaging agent for imaging tissue in a subject, a gamma-emitting radioisotope, e.g., 203 There is provided the use of a SPECT imaging agent comprising a compound of formula (1) as described herein complexed to Pb.

[0279] The amount of imaging agent administered to a subject depends on several physiological factors known to physicians, including the nature of the imaging being performed, the tissue targeted for imaging or treatment, and the weight and medical history of the subject being imaged or treated with the radiopharmaceutical.

[0280] Method for preparing compounds of formula (1) The present disclosure also provides a compound of formula (1): [ka] (In the formula, n, A, L 1 , L 2 , X 1 , X 2 , X 3 , R 1 , R 2 and R M is as described herein), or a salt thereof. It will be understood that the embodiments and examples of compounds of formula (1), including any one of formulas (1A) to (1L), described herein are equally applicable to the methods described herein.

[0281] A and X 1 or its analogues or derivatives, X 1 and L 1 or its analogues or derivatives, L 1 and X 2 or its analogues or derivatives, X 2 and R 1 between the carbon atom to which X is attached or its analogue or derivative, 3 and R 2 between the carbon atom to which X is attached or its analogue or derivative, 3 and R 1 between the carbon atom to which n is attached or an analog or derivative thereof (e.g., when n is 0), L 2 and R 2 between the carbon atom to which X is attached or its analogue or derivative (e.g., X 3 does not exist), L 2 and R 1 between the carbon atom to which X is attached or its analogue or derivative (e.g., X 3 does not exist and n is 0), X 3 and L 2 or its analogues or derivatives, L 2 and R M or its analogues or derivatives, X 3 and R Mor its analogues or derivatives (L 2 Any manner of forming a covalent bond between (where X is an integer greater than 1 and X is an integer greater than 2) (including any intervening heteroatoms) can be utilized in accordance with the present invention. Each covalent bond can be formed by direct conjugation of any of these molecules or analogs or derivatives thereof.

[0282] While not intending to limit the scope of the present disclosure, covalent bonds can occur, for example, between acid, acid chloride, aldehyde, hydroxy, amino, alcohol, alkyl halide, sulfhydryl, or hydrazo groups by forming, for example, an amide, ester, ether, thioether, disulfide, imino, or sulfonamide group. Other suitable reactions include, but are not limited to, O-alkylation (etherification), N-alkylation, C-alkylation, chiral alkylation, S-alkylation, esterification, transesterification, substitution (e.g., with cyanide, hydroxide, fluoride, thiocyanate, cyanate, iodide, sulfide, sulfite, azide, nitrite, or nitrate), other nucleophilic aliphatic and aromatic substitutions, oxidation, hydrolysis, epoxidation and chiral epoxidation, Michael addition, aldol condensation, Wittig condensation, Darzens condensation, carbene reaction, thiophosphorylation, reduction, carbonylation, transition metal cocatalysis, HCl / HBr / HOCl / H2SO4 reaction. One skilled in the art will appreciate that the suitability of a reaction for forming a covalent bond can be determined by the n, A, L 1 , L 2 , X 1 , X 2 , X 3 , R 1 , R 2 and R M It will be understood that the selection of A, L, and functional groups present on any synthetic intermediates will be dependent upon the selection of A, L, and functional groups present on any synthetic intermediates. 1 , L 2 , X 1 , X 2 , X 3 , R 1 , R 2 , R MIt will be appreciated that several synthetic methods are available for the synthesis of these and their analogs or derivatives, or in many cases such molecules may be commercially available. Suitable examples include, but are not limited to, amino acids, peptides, amino alcohols, polyethylene glycols, alkanes, alkenes, alkynes, azido aromatic compounds, carbohydrates, carboxylic acids, esters, organophosphorus compounds, and sulfonates.

[0283] Those skilled in the art will appreciate that the overall synthetic method, as well as any particular reaction or step therein, is fully understood to be within the scope of the present invention, and will be understood to be within the scope of the present invention, as defined herein, of the variables n, A, L, which may include optional substituents and / or interruptions. 1 , L 2 , X 1 , X 2 , X 3 , R 1 , R 2 , and R M It will be understood that the bond-forming reaction may be selected depending on the selection of the group. Non-limiting examples of suitable bond-forming reactions are described in Richard C. Larock (ed.), "Comprehensive Organic Transformations: A Guide to Functional Group Preparations," 4th edition, John Wiley & Sons (2018), and Theodora E. Greene and Peter G.M.Wuts, "Protective Groups in Organic Synthesis," 2nd edition, John Wiley & Sons, Inc. New York (1991), the contents of which are incorporated herein in their entireties.

[0284] In one embodiment, the method comprises reacting a compound of formula (1L) [ka] or a salt, solvate or stereoisomer thereof, comprising In the formula, n, L 2 , X 3 , R1 , and R 2 is as described herein.

[0285] It will be appreciated that the synthesis of compounds of formula (1L) can be accomplished by one or more coupling steps. Those skilled in the art will appreciate that each amide bond present in compounds of formula (1L) can be formed via an amide bond-forming reaction between an activated carboxylic acid, acid chloride, or mixed anhydride and an amine. In accordance with the above, X 3 and R 2 or the carbon atom to which R is attached 1 Any manner of forming a covalent bond between X and any of the carbon atoms to which it is attached (when n is 0) can be utilized. 3 If there is no L 2 and R 2 or the carbon atom to which R is attached 1 Any manner of forming a covalent bond between L and either of the carbon atoms to which it is attached (when n is 0) may be utilized. 2 Any manner of forming a covalent bond between L and the cyclic N may be utilized. 2 If does not exist, X 3 Any manner of forming a covalent bond between the ring N and the ring N may be utilized.

[0286] In some embodiments, at least one, two, three, four, five, or six or more of the coupling steps are amide couplings. It will also be understood that synthesis of a compound of Formula (1L) may further require one, two, three, four, or five or more deprotection steps. The deprotection step comprises removal of at least one protecting group. In some embodiments, the deprotection step comprises removal of at least one Fmoc group. In some embodiments, the deprotection step comprises removal of at least one Dde group. The one or more coupling steps and the one or more deprotection steps may be carried out as a series of solution-phase reactions, a series of reactions carried out on a solid support (i.e., at least one of the reactants in each step is supported on a resin), or a combination thereof. In some embodiments, the method is carried out at least partially on a solid support. In some embodiments, the method is carried out at least partially without a solid support. The terms "solid phase" or "solid support" refer to any solid material or support on which peptides can be synthesized, for example, via solid phase peptide synthesis (SPPS). In some embodiments, the method is carried out at least in part via solid phase peptide synthesis. In some embodiments, the method is carried out at least in part via Fmoc solid phase peptide synthesis. Solid phase peptide synthesis, including solid phase peptide synthesis of a compound of Formula (1L), can be carried out manually or using automated equipment such as a peptide synthesizer.

[0287] Suitable resins for solid-phase synthesis include chloro- and bromo-functionalized (Merrifield, 4-bromomethylphenoxy)methyl polystyrene, 2-(4-bromomethylphenoxy)ethyl polystyrene, trityl, 2-chlorotrityl chloride, NovaSyn TGT Alcohol, NovaSyn TGT Bromo), amino- and hydrazine-functionalized (AM polystyrene and N-methylaminomethyl polystyrene, NovaSyn TG Amino, MBHA polystyrene, Rink Amide, Siber, aminotrityl, sulfamyl base, Weinreb AM, Fmoc-4-hydrazinobenzoyl, NOVAGel, alkylaminomethyl indole, hydroxylamine Wang), hydroxyl-functionalized (NovSyn hydroxyl, hydroxymethylphenyl, oxime), carboxy, aldehyde (benzyloxybenzaldehyde, FMPB AM, FMPB NovaGel, NOVAPEG FMBP, FMPE, DFPE, 3-formylindoyl) acetamidomethyl polystyrene-FIA. The solid phase may be selected from the group consisting of: AM resin), enol-functionalized (DHP HM resin), thiol-functionalized (mercaptomethyl, 3-[4-tritylmercapto)phenylpropionyl AM resin), carbonate-functionalized, and alkenylcarbonyl-functionalized. The resin may be pre-functionalized with one or more amino acids or derivatized amino acids (which may be referred to as resin-bound derivatives), such as those described herein. In some embodiments, the solid phase is any resin suitable for solid-phase peptide synthesis. In some embodiments, the solid phase is an acid-labile resin. In some embodiments, the solid phase is a 2-chlorotrityl chloride resin. In some embodiments, the compound of Formula 1L, its precursor, or derivative is linked to the solid support via the 2-chlorotrityl moiety. It will be understood that the solid support typically carries a plurality of compounds of Formula 1L, their precursors, or derivatives.

[0288] In some embodiments, one or more coupling steps are carried out using standard solid-phase peptide-compatible conditions. Suitable Fmoc-compatible conditions are described in Chen, W C and White, P D 'Fmoc Solid Phase Peptide Synthesis: A Practical Approach' 2000 (Oxford University Press; Hames, B D (Ed.)) ISBN 0199637245, the contents of which are incorporated herein by reference in their entirety. Suitable conditions typically involve coupling the amine reactant with a carboxyl reactant, which is presented as an appropriately substituted carboxylic acid (typically in activated form, such as an acid chloride, mixed anhydride, etc.), or with one or more coupling reagents suitable for forming an amide bond, such as 1,1-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), hydroxybenzothiazole (HOBt), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 [-b]pyridinium 3-oxide hexafluorophosphate (HATU), [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium hexafluorophosphate (HBTU), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), or the like (optionally with 4-dimethylaminopyridine (DMAP), diisopropylethylamine (DIPEA), or ethyl cyano(hydroxyimino)acetate (OxymaPure®)) to form an amide bond. In some embodiments, one or more coupling steps are carried out using any coupling reagent suitable for forming an amide bond. In some embodiments, one or more coupling steps are carried out using CDI, DIC, PyBOP, HBTU, or HATU. Suitable solvents include, but are not limited to, DMF, DCM, and combinations thereof.The reaction can also be carried out at elevated temperatures, achieved either by heating (e.g., to a temperature of about 30-70°C) or by microwave irradiation. The reaction can also be carried out with constant or periodic stirring. It should be understood that independent conditions and reagents can be selected for each coupling step. Contact of the two reagents can be carried out for any particular length of time, from 1 minute to 24 hours, and one of skill in the art will understand that this can be optimized depending on the choice of reaction conditions, reagents, and reactants.

[0289] In some embodiments, one or more coupling steps are carried out with a coupling reagent used in a molar excess relative to at least about 1, 1.1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 25, 50, 100, or 1000 molar equivalents of the conjugated species. In some embodiments, one or more coupling steps are carried out with a catalyst or base used in a molar excess relative to at least about 1, 1.1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 25, 50, 100, or 1000 molar equivalents of the conjugated species. In some embodiments, the coupling reagent, catalyst, and base can be used in a molar excess relative to the conjugated species ranging between any of the above values, e.g., from about 1 to about 1000 molar equivalents, or from about 2 to about 20 molar equivalents.

[0290] Optionally, the solid phase synthesis methods described herein may include a capping step (e.g., with an excess of acetic anhydride or other activated capping agent) after each coupling step to cap any unprotected sites and prevent the synthesis of compounds that may lack a single moiety that may be difficult to separate from the desired product.

[0291] In some embodiments, the method comprises: 1 -Lys(PG 2 )-OH or H-Lys(PG 2 In some embodiments, the method comprises providing PG 1 -Lys(PG 2)-OH or H-Lys(PG 2 )-OH or a salt or resin-bound derivative thereof, 1 and P.G. 2 are independent amine protecting groups. In some embodiments, PG 1 -Lys(PG 2 )-OH or H-Lys(PG 2)-OH is its L-stereoisomer. The term "amine protecting group," as used herein, is intended to refer to a group that can be easily removed to provide the corresponding NH or NH group of the amine, which protects the amine group from undesired reactions that might otherwise occur during synthetic procedures. Such protecting groups are described in "Protective Groups in Organic Synthesis" edited by T.W. Greene et al. (John Wiley & Sons, 1999) and "Amino Acid-Protecting Groups" by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455-2504, the contents of which are incorporated herein by reference in their entireties. Non-limiting examples of amine protecting groups include acyl and acyloxy groups, such as acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxy-acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, picolinoyl, aminocaproyl, benzoyl, methoxy-carbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, tert-butyloxycarbonyl (BOC), allyloxycarbonyl (alloc), benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichloro-benzyloxycarbonyl, and the like. Further examples include Cbz (carboxybenzyl), Nosyl (o- or p-nitrophenylsulfonyl), Bpoc (2-(4-biphenyl)isopropoxycarbonyl), and Dde (1-(4,4-dimethyl-2,6-dioxohexylidene)ethyl). In some embodiments, PG 1 and P.G. 2 are different amine protecting groups. In some embodiments, PG 1 is Fmoc. In some embodiments, PG 2is an amine protecting group that can be selectively removed in the presence of an Fmoc protecting group. In some embodiments, PG 2 is Dde.

[0292] In one embodiment, the method comprises administering to a subject a subject in need thereof a therapeutically effective amount of H-Glu(PG 3 )-O-PG 4 PG 3 and P.G. 4 is an independent carboxyl protecting group. In some embodiments, H-Glu(PG 3 )-O-PG 4 is its L-stereoisomer. The term "carboxyl-protecting group," as used herein, is intended to refer to a group that can be easily removed to provide a COOH group, protecting the carboxyl group from undesired reactions that might otherwise occur during synthetic procedures. Such protecting groups are described in "Protective Groups in Organic Synthesis," edited by T.W. Greene et al. (John Wiley & Sons, 1999) and "Amino Acid-Protecting Groups" by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez), Chemical Reviews 2009 (109) 2455-2504. Non-limiting examples of carboxyl-protecting groups include alkyl and silyl groups, such as methyl, ethyl, tert-, butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, and tert-butyldimethylsilyl. In one embodiment, PG 3 and P.G. 4 are the same carboxyl protecting group. In some embodiments, PG 3 is tert-Bu. In some embodiments, PG 4 is tert-Bu. In some embodiments, PG 3 and P.G. 4 is tert-Bu.

[0293] In one embodiment, the method comprises a coupling step with suberic acid. 5 -Lys-O-PG 6 PG 5 is an amine protecting group, and PG 6 is a carboxyl protecting group. In some embodiments, PG 5 -Lys-O-PG 6 is its D stereoisomer. In some embodiments, PG 5 is Fmoc. In some embodiments, PG 6 is tert-Bu.

[0294] In one embodiment, the method comprises: 7 -NH-CH(R 1 )-COOH coupling step, and PG 7 is an amine protecting group and R 1 is as described herein. In some embodiments, PG 7 -NH-CH(R 1 )-COOH is its D stereoisomer. In some embodiments, PG 7 is Fmoc. In one embodiment, the method comprises: 7 -Phe-OH coupling step with PG 7 is an amine protecting group.

[0295] In one embodiment, the method optionally comprises: 8 -NH-CH(R 2 )-COOH, and one or more coupling steps with PG 8 is an amine protecting group and R 2 is as described herein. In one embodiment, the method comprises: 8 -NH-CH(R 2 )-COOH, and one or more coupling steps with PG 8 is an amine protecting group and R 2is as described herein. In some embodiments, PG 8 -NH-CH(R 2 )-COOH is its D-stereoisomer. In some embodiments, PG 8 is Fmoc. In one embodiment, the method comprises: 8 -3-iodo-Tyr-OH, and one or more coupling steps with PG 8 is an amine protecting group. 8 -NH-CH(R 2 )-COOH, each coupling step is followed by PG 8 It should be understood that a step of removing the protecting group may also be performed. That is, in some embodiments, the method comprises: 8 -NH-CH(R 2 )-COOH, and optionally one, two or three coupling steps with PG 8 Optionally, one, two or three deprotection steps are included to remove protecting groups.

[0296] In one embodiment, the method comprises the step of: [ka] (In the formula, RG 1 is a reactive coupling group, and L 2 and R M includes a coupling step with a compound of formula (described herein).

[0297] In one embodiment, the method comprises the step of: [ka] (In the formula, RG 2 is a reactive coupling group, and n, A, X 1 , L 1 , X 2 , R 1 and R 2 (wherein R is as defined herein) with a compound of formula (I).

[0298] In one embodiment, the compound of formula (S-1) is optionally attached to a solid support. For example, A can be its solid support derivative. In some embodiments, the compound of formula (S-1) is attached to a solid support (i.e., is a solid support derivative of formula S-1). Those skilled in the art will understand that various positions can be selected for attachment to a solid support.

[0299] It will be understood that a reactive coupling group refers to a functional group suitable for carrying out a coupling step or reaction. A reactive coupling group is suitable for carrying out coupling with certain other reactive coupling groups, and one skilled in the art will be able to select an appropriate pair of complementary reactive coupling groups (i.e., RG as used herein) for carrying out a coupling step or reaction. 1 and R.G. 2 It will be understood that suitable combinations of can be selected. Non-limiting examples of suitable reactive coupling groups can include, but are not limited to, epoxides, peroxides, alkylboranes, halides, thiols, amines, amides, aldehydes, -OH, -COOH, esters, diazo, isocyanates, silanes, phosphorus-containing groups, dithioesters, dithiocarbamates, dithiocarbonates, trithiocarbonates, alkoxyamines, formyl azides, sulfonyl halides, arylsulfonyl groups (such as arylsulfonyl halides or arylsulfonyl azides), phosphoryl azides, vinyls (such as vinyl, alkyl vinyl, vinylidene, or aryl vinyl), dienes, dyes, porphyrins, alkyl azides, aryl azides, or combinations or derivatives thereof. In some embodiments, RG 1 and R.G. 2 are each independently selected from a thiol, an amine, an amide, an aldehyde, —OH, —COOH, an ester, a dithiocarbonate, a diazo, or a sulfonyl halide. 1 and R.G. 2are each independently selected from an amine, an amide, an aldehyde, —OH, —COOH, and an ester. 1 and R.G. 2 are each independently selected from an amine, an amide, an aldehyde, —OH, and —COOH. 1 and R.G. 2 are each independently selected from an amine and —COOH. 1 is -COOH and RG 2 is an amine.

[0300] In one embodiment, the method comprises coupling a compound of formula (R-1) with a compound of formula (S-1): RG 1 and R.G. 2 It will be understood that may be coupled together (e.g., reacted together) to form a compound of formula (1) comprising any one of formulas (1A) to (1L).

[0301] In one embodiment, there is provided a method for preparing a compound of formula (1), including any one of the compounds of formulae (1A) to (1L), or a salt or solid-supported derivative thereof, comprising coupling a compound of formula (R-1) with a compound of formula (S-1): [ka] (In the formula, RG 1 and R.G. 2 are each independently a reactive coupling group; n, A, X 1 , L 1 , X 2 , R 1 , R 2 , L 2 , and R M are described herein) A method is provided wherein the compound of formula (S-1) is optionally attached to a solid support.

[0302] It will be appreciated that the compound of (S-1) and the compound of (R-1) are coupled together to form a compound of formula (1), which includes any one of the compounds of formulas (1A) to (1L). In one embodiment, RG 1 and R.G. 2 are coupled together to form X in a compound of formula (1) including any one of the compounds of formulas (1A) to (1L). 3 In one embodiment, A is a solid support derivative thereof.

[0303] In one embodiment, compound (R-1) has formula (R-2): [ka] (In the formula, RG 1 is a reactive coupling group, and L 2 has the structure described herein).

[0304] In one embodiment, the compound of (S-1) has the formula (S-2): [ka] (In the formula, RG 2 is a reactive coupling group, n, R 1 and R 2 has the structure:

[0305] In some embodiments, the compound of formula (S-1) is optionally attached to a solid support. In some embodiments, the compound of formula (S-2) is attached to a solid support (i.e., is a solid-supported derivative of formula S-1). Those skilled in the art will appreciate that various positions can be selected for attachment to the solid support. In some embodiments, the compound is attached to the solid support via an amino acid carboxylic acid. In some embodiments, the compound is attached to the solid support via a lysine carboxylic acid.

[0306] In one embodiment, there is provided a method for preparing a compound of formula (1L), or a salt or solid supported derivative thereof, comprising coupling a compound of formula (R-2) with a compound of formula (S-2): [ka] (In the formula, RG 1 and R.G. 2 are each independently a reactive coupling group; n, L 2 , R 1 , and R 2 are described herein) A method is provided wherein the compound of formula (S-2) is optionally attached to a solid support.

[0307] In one embodiment, the compound of (S-1) has the formula (S-2A): [ka] (In the formula, [ka] indicates a solid support, RG 2 is a reactive coupling group, n, R 1 and R 2 has the structure:

[0308] In one embodiment, there is provided a method for preparing a compound of formula (1L), or a salt or solid supported derivative thereof, comprising coupling a compound of formula (R-2) with a compound of formula (S-2) or (S-2A): [ka] (In the formula, [ka] indicates a solid support, RG 1and R.G. 2 are each independently a reactive coupling group; n, R 1 , R 2 and L 2 is defined herein).

[0309] It will be appreciated that compound (R-2) is coupled with compound (S-2) or (S-2A) to form a compound of formula (1L). In one embodiment, the coupling occurs at X in compound of formula (1L). 3 Form.

[0310] In one embodiment, the method comprises the step of forming a compound of formula (R-3) or (R-4): [ka] (In the formula, R 19 is as described herein, and PG 9 is a carboxyl protecting group). In some embodiments, PG 9 is tert-Bu.

[0311] In one embodiment, there is provided a method for preparing a compound of formula (1L), or a salt or solid supported derivative thereof, comprising coupling a compound of formula (R-3) with a compound of formula (S-2) or (S-2A): [ka] (In the formula, [ka] indicates a solid support, RG 1 and R.G. 2 are each independently a reactive coupling group; n, R 1 , R 2 and R 19 is defined herein).

[0312] It will be appreciated that compound (R-3) is coupled with compound (S-2) or (S-2A) to form a compound of formula (1L). In one embodiment, the coupling occurs at X in compound of formula (1L). 3 Form.

[0313] In one embodiment, there is provided a method for preparing a compound of formula (1L), or a salt or solid supported derivative thereof, comprising coupling a compound of formula (R-4) with a compound of formula (S-2) or (S-2A): [ka] (In the formula, [ka] indicates a solid support, RG 1 and R.G. 2 are each independently a reactive coupling group; n, R 1 , R 2 , R 19 , and P.G. 9 is defined herein).

[0314] It will be appreciated that compound (R-4) is coupled with compound (S-2) or (S-2A) to form a compound of formula (1L). In one embodiment, the coupling occurs at X in compound of formula (1L). 3 Form.

[0315] In one embodiment, the method comprises reacting a compound of formula (R-5): [ka] (In the formula, PG 9 is a carboxyl protecting group). In some embodiments, PG 9 is tert-Bu.

[0316] In one embodiment, there is provided a method for preparing a compound of formula (1L), or a salt or solid supported derivative thereof, comprising reacting a compound of formula (R-5) with a compound of formula (S-2) or (S-2A): [ka] (In the formula, [ka] indicates a solid support, RG 1 and R.G. 2 are each independently a reactive coupling group; n, R 1 , R 2 and P.G. 9 is defined herein).

[0317] It will be appreciated that compound (R-5) is coupled with compound (S-2) or (S-2A) to form a compound of formula (1L). In one embodiment, the coupling occurs at X in compound of formula (1L). 3 Form.

[0318] Those skilled in the art will appreciate that compounds having the structures R-1, R-2, R-3, R-4, and R-5 can be readily prepared from DO3AM. The full chemical name for DO3AM is 1,4,7,10-tetraazaicyclododecane-1,4,7-triacetamide; 2,2',2"-(1,4,7,10-tetraazaicyclododecane-1,4,7-triyl)triacetamide. While not intending to limit the scope of any of the aspects, embodiments, or examples described herein, compounds of R-1, R-2, R-3, or R-4 can be prepared, for example, by synthesizing HOOC-R 19 -X, HOOC-R 19 -CH(COO-PG 9 )X, or HOOCCH2CH2CH(COO-PG 9 )X (wherein X is a halide (e.g., Br, Cl, and I) and R 19may be prepared by nucleophilic substitution with (as described according to any aspect, embodiment, or example described herein).

[0319] The conditions for carrying out the deprotection step depend on the selection of protecting groups and the desired site of deprotection. Typically, deprotection involves treating the protected compound (which may be bound to a solid support) with an acid, base (e.g., secondary amines, primary amines, piperidine, piperazine, 1,8-diazabicyclo[5.4.0]undec-7-ene), metal catalyst, or other reactive compounds such as hydrazine for a period of time. Deprotection can also be carried out at elevated temperatures, achieved either by heating (e.g., to a temperature of about 30-70°C) or microwave irradiation. Deprotection can also be carried out with constant or periodic stirring. There are usually several conditions under which a protecting group can be cleaved, and one skilled in the art will be able to determine appropriate conditions depending on the solid support selected, the protecting group to be removed, and the remaining functional groups in the compound (including other protecting groups present). Selective deprotection steps include cleavage of a protecting group in the presence of one or more additional protecting groups, e.g., PG 1 PG in the presence of 2 Therefore, in some embodiments, it is necessary to select conditions that allow deprotection of PG. 1 PG 2 In some embodiments, PG 1 , P.G. 5 , P.G. 7 , and P.G. 8 are the same.

[0320] In some embodiments, the method comprises: 1 In some embodiments, the method comprises removing the protecting group. 2 In some embodiments, the method comprises removing the protecting group. 3 In some embodiments, the method comprises removing the protecting group. 4 In some embodiments, the method comprises removing the protecting group. 5 In some embodiments, the method comprises removing the protecting group.6 In some embodiments, the method comprises removing the protecting group. 7 In some embodiments, the method comprises removing the protecting group. 8 In some embodiments, the method comprises removing the protecting group. 8 In some embodiments, the method further comprises one or more steps including removing a protecting group. 9 In some embodiments, the PG 1 , P.G. 5 , P.G. 7 or PG 8 Removing the protecting group comprises contacting the molecule containing the protecting group with a base. 1 , P.G. 5 , P.G. 7 or PG 8 Removing the protecting group comprises contacting the molecule containing the protecting group with a solution containing piperidine (e.g., a 20% piperidine solution in DMF). In some embodiments, PG 2 Removing the protecting group involves contacting the molecule containing the protecting group with a solution containing hydrazine. It will be appreciated that multiple deprotection steps may be necessary to achieve complete removal of the protecting group, and various methods for monitoring completion are known in the art.

[0321] In some embodiments, the method comprises: (a)PG 1 -Lys(PG 2 )-OH or H-Lys(PG 2 )—OH or a salt thereof or a resin-bound derivative thereof; (b) Optionally, if present, PG 1 removing the protecting group; (c) H-Glu(PG 3 )-O-PG 4 or a salt thereof; (d)PG 2 removing the protecting group; (e) coupling to suberic acid or a salt thereof; (f)PG 5 -Lys-O-PG 6 or a salt thereof; (g)PG 5 removing the protecting group; (h)PG 7 -NH-CH(R 1 )-COOH or a salt thereof; (i)PG 7 removing the protecting group; (j) Optionally, PG 8 -NH-CH(R 2 )-COOH or a salt thereof; (k) Optionally, if present, PG 8 removing the protecting group; (l) optionally repeating step (j) followed by step (k) one or two times; and (m) coupling to compounds R-1, R-2, R-3, R-4, R-5 or salts thereof; and / or consisting of PG 1 , P.G. 2 , P.G. 3 , P.G. 4 , P.G. 5 , P.G. 6 , P.G. 7 , P.G. 8 , and P.G. 9 is as described herein.

[0322] In some embodiments, the method comprises: (a)PG 1 -Lys(PG 2 )-OH or H-Lys(PG 2 )—OH or a salt thereof or a resin-bound derivative thereof; (c) H-Glu(PG 3 )-O-PG 4 or a salt thereof; (e) coupling to suberic acid or a salt thereof; (f)PG5 -Lys-O-PG 6 or a salt thereof; (h)PG 7 -NH-CH(R 1 )-COOH or a salt thereof; (j)PG 8 -NH-CH(R 2 )-COOH or a salt thereof; (l) optionally repeating step (j) one or two times; and (m) coupling to a compound of R-1, R-2, R-3, R-4, R-5 or a salt thereof; PG 1 , P.G. 2 , P.G. 3 , P.G. 4 , P.G. 5 , P.G. 6 , P.G. 7 , P.G. 8 , and P.G. 9 is as described herein.

[0323] In some embodiments, the method comprises: (a)PG 1 -Lys(PG 2 )-OH or H-Lys(PG 2 )—OH or a salt thereof or a resin-bound derivative thereof; (b) Optionally, if present, PG 1 removing the protecting group; (c) H-Glu(PG 3 )-O-PG 4 or a salt thereof; (d)PG 2 removing the protecting group; (e) coupling to suberic acid or a salt thereof; (f)PG 5 -Lys-O-PG 6 or a salt thereof; (g)PG 5removing the protecting group; (h)PG 7 -NH-CH(R 1 )-COOH or a salt thereof; (i)PG 7 removing the protecting group; (j) Optionally, PG 8 -NH-CH(R 2 )-COOH or a salt thereof; (k) Optionally, if present, PG 8 removing the protecting group; (l) optionally repeating step (j) followed by step (k) one or two times; and (m) coupling to compounds R-1, R-2, R-3, R-4, R-5 or salts thereof; (n) optionally cleaving the synthesized peptide from the resin to obtain a crude peptide, and optionally precipitating it; and (o) optionally purifying the crude peptide to obtain a pure product; and / or consisting of PG 1 , P.G. 2 , P.G. 3 , P.G. 4 , P.G. 5 , P.G. 6 , P.G. 7 , P.G. 8 , and P.G. 9 is as described herein.

[0324] Those skilled in the art will recognize that the order in which steps (a) through (o) are performed may be varied, and that multiple variations are possible to prepare the same desired compound, i.e., the order of the coupling steps may be varied, yet still result in the same compound of Formula (1) or Formulas (1A) through (1L).

[0325] In some embodiments, PG 1 -Lys(PG 2 )-OH or H-Lys(PG 2 )-OH is attached to a solid support. In some embodiments, PG1 -Lys(PG 2 )-OH or H-Lys(PG 2 Providing )-OH is PG 1 -Lys(PG 2 )-OH or H-Lys(PG 2 )-OH to a solid support. In some embodiments, 2 Providing )-OH is PG 1 -Lys(PG 2 )-OH to PG 1 This involves removing the protecting groups.

[0326] In some embodiments, the method comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amide coupling steps, hi some embodiments, all of the coupling steps are amide coupling steps.

[0327] In some embodiments, the method further comprises cleaving the synthesized peptide from the solid support or resin to obtain a crude peptide. Thus, in some embodiments, the method is a method for providing a synthesized peptide. The conditions required to cleave the growing compound from the solid support depend on the solid support selected. Typically, the cleavage conditions comprise exposing the resin to a composition comprising an acid (e.g., trifluoroacetic acid, also known as TFA) or base, water, and optionally a scavenger (e.g., triisopropylsilane, also known as TIPS) and / or a reducing agent (e.g., EDTA or DTT), optionally at elevated temperature. In some embodiments, the conditions for cleaving the compound from the solid support also allow for the global deprotection of any remaining protecting groups (e.g., tert-Bu carboxyl protecting groups) on the compound. The resulting crude peptide can optionally be precipitated from the cleavage mixture by adding a solvent, such as diethyl ether, followed by separation by centrifugation and filtration. The crude peptide can be lyophilized.

[0328] In one embodiment, the method further comprises purifying the crude peptide to obtain a pure product. The peptide may be purified by any means known in the art, for example, by one or more chromatography methods, one or more filtration methods, one or more electrophoresis methods, one or more precipitation-based methods, and / or one or more dialysis methods. In one embodiment, purifying the crude peptide comprises one or more chromatography methods. In one embodiment, purifying the crude peptide comprises one or more precipitation-based methods. In one embodiment, purifying the crude peptide comprises reverse-phase high performance liquid chromatography. In one embodiment, purifying the crude peptide comprises one or more precipitation-based methods and reverse-phase high performance liquid chromatography. It is understood that one or more counterions may be introduced during peptide synthesis and / or purification, e.g., trifluoroacetate or phosphate. One of skill in the art will appreciate that at some point during or after peptide synthesis and / or purification, it may be desirable to replace the peptide counterion with a pharmaceutically acceptable counterion, such as, for example, acetate or chloride. Counterions may be replaced by any means known in the art for ion exchange, including, but not limited to, ion exchange chromatography, precipitation-based methods, dialysis, ultrafiltration, chemical reactions, and combinations thereof.

[0329] In some embodiments, the method provides a compound of Formula (1) with a purity (%) of at least about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 98.

[0330] In some embodiments, the method provides a compound of Formula (1) in at least about 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 98% yield.

[0331] In some embodiments, the method is for the preparation of a compound of formula (1), wherein the compound is [ka] or a salt, solvate or stereoisomer thereof.

[0332] In some embodiments, the method is for the preparation of a compound of formula (1), wherein the compound is [ka] or a salt, solvate or stereoisomer thereof.

[0333] In some embodiments, the method further comprises radiolabeling the compound of Formula (1) with a radioisotope, which may be any radioisotope described herein. In some embodiments, radiolabeling the compound of Formula (1) with the radioisotope comprises contacting the compound of Formula (1) with a solution comprising the radioisotope. In some embodiments, the solution comprising the radioisotope comprises the radioisotope as a salt, e.g., a chloride salt. In some embodiments, contacting the compound of Formula (1) with the solution comprising the radioisotope is performed for a period (minutes) greater than about 1, 5, 10, 30, 60, 120, 180, or 360. In some embodiments, contacting the compound of Formula (1) with the solution comprising the radioisotope is performed at ambient temperature. In some embodiments, contacting the compound of Formula (1) with the solution comprising the radioisotope is performed at a temperature greater than ambient temperature. In some embodiments, the solution comprising the radioisotope has a pH greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, the solution comprising the radioisotope comprises a substantially aqueous solvent. In some embodiments, the solution comprising the radioisotope comprises a substantially acetate aqueous solvent. ***

[0334] The present disclosure can also be described by reference to one or more of the following exemplary embodiments. It will be understood that the specific embodiments presented below are not intended to limit the scope. Those skilled in the art will understand that one or more of the elements, features, or embodiments listed below (and indeed any such aspects or embodiments described herein) can be combined in combinations not specifically set forth herein. All such embodiments are considered to be within the scope of the present disclosure.

[0335] 1.Equation (1) [ka] (In the formula, n is 0 to 3, A is a PSMA-targeting ligand; X 1 ~X 3 are each independently absent, or —O—, —S—, —C(═O)—, or —C(═O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3 -, -S(=O)NR 3 -, -OS(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, L 1 and L 2 are each independently absent or a divalent linking moiety; R 1 and each R 2 is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl, each of which is optionally substituted; R 3is selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted; R M is the formula (M-1) [ka] (In the formula, Y 1 ~Y 4 are each independently an optionally substituted -C 1~6 alkyl-, R 4 ~R 7 are each independently -C(=O)N(R 3 )2, -P(=O)(OR 3 )2, -P(=O)OR 3 (R 3 ), -P(=O)(R 3 )2, -C 1~10 AlkylC(=O)N(R 3 )2, -C 1~10 AlkylP(=O)(OR 3 )2, -C 1~10 AlkylP(=O)OR 3 (R 3 ) and -C 1~10 AlkylP(=O)(R 3 )2, or R 4 and R 6 or R 5 and R 7 One of them, together, forms -(CH2) m - forming a cross-link, each C 1~10 The alkyl is optionally substituted; L 3 is absent or is not a ring heteroatom or Y 1 ~Y 4 The ring is connected to L of formula (1) via one of 2 is a bivalent linking moiety that connects to [ka] is R M L in equation (1)2 represents the bond that attaches m is 1 to 3), R M is optionally conjugated to a radioisotope), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0336] 2.X 1 ~X 3 each independently represents either absent, —O—, —S—, —C(═O)—, or —C(═O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -S(=O)2NR 3 -, -S(=O)NR 3 -, -OS(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, R 1 and each R 2 is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl; R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl; R 4 ~R 7 are each independently -C(=O)N(R 3 )2, -P(=O)(OR 3 )2, -P(=O)OR 3 (R 3 ), -P(=O)(R 3 )2, -C 1~10 AlkylC(=O)N(R 3 )2, -C 1~10 AlkylP(=O)(OR 3 )2, -C 1~10 AlkylP(=O)OR 3 (R 3 ) and -C 1~10AlkylP(=O)(R 3 )2, or R 4 and R 6 or R 5 and R 7 One of them, together, forms -(CH2) m - forming a cross-link, each C 1~10 The alkyl may be one or more R 8 is optionally replaced by Y 1 ~Y 4 However, each independently, -C 1~6 alkyl-, Y 1 ~Y 4 and R 1 ~R 7 Each of the 8 is optionally replaced by Each R 8 are independently H, halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -NO2, -CN, -SCN, -N3, =O, -N(R 9 )2, -C(=O)N(R 9 )2, -S(=O)N(R 9 )2, -S(=O)2N(R 9 )2, -OR 9 , -SR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , -S(=O)R 9 , -S(=O)2R 9 , -S(=O)OR 9 , -S(=O)2OR 9 , -S(=O)(OR9 )2, -OS(=O)R 9 , -OS(=O)2R 9 , -OS(=O)OR9, -OS(=O)2OR 9 , -OS(=O)(OR 9 )2, -N(R 9 )C(=O)R 9 , -N(R 9 )S(=O)R 9 , -N(R 9 )C(=O)N(R 9 )2, -N(R 9 )S(=O)2R 9 , -P(=O)(OR 9 )2, -P(=O)OR 9 (R 9 ), -P(=O)(R 9 )2, -OP(=O)(OR 9 )2, -OP(=O)OR 9 (R 9 ) and -OP(=O)(R 9 )2, wherein each C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl are each independently selected from the group consisting of one or more R 10 is optionally replaced by Each R 9 However, independently, H, C 1~6 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~6 Alkyl-3 to 10-membered carbocyclyl, and C 1~6 alkyl-3 to 10-membered heterocyclyl, and each C 1~6 Alkyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl are each independently selected from the group consisting of one or more R 10 is optionally replaced by Each R 10 are independently H, halogen, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -C(=O)N(R 11)2, -N(R 11 )C(=O)R 11 , -OR 11 , -P(=O)(OR 11 )2, -P(=O)OR 11 (R 11 ), -P(=O)(R 11 )2, C 1~6 Alkyl and -OC 1~6 is selected from the group consisting of alkyl, Each R 11 However, independently, H, C 1~10 Alkyl, C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 The compound of exemplary embodiment 1, wherein the aryl group is selected from the group consisting of alkyl-3- to 10-membered heterocyclyl.

[0337] 3.R M However, equations (M-1A) to (M-1D): [ka] (In the formula, R 4 ~R 7 are each independently -C(=O)N(R 14 )2, -P(=O)(OR 14 )2, -P(=O)OR 3 (R 14 ), -P(=O)(R 14 )2, -C 1~10 AlkylC(=O)N(R 14 )2, -C 1~10 AlkylP(=O)(OR 14 )2, -C 1~10 AlkylP(=O)OR 14 (R 14 ) and -C 1~10 AlkylP(=O)(R 14 )2, or R 4 and R 6 or R 5 and R 7One of them, together, forms -(CH2) m - forming a cross-link, each C 1~6 The alkyl may be one or more R 8 is optionally replaced by R 12 and R 13 are each independently H, -C(=O)OR 14 , -C(=O)N(R 14 )2, -C 1~6 AlkylC(=O)OR 14 , -C 1~6 AlkylC(=O)N(R 14 )2, -P(=O)(OR 14 )2-P(=O)OR 14 (R 14 ), -P(=O)(R 14 )2, -C 1~6 AlkylP(=O)OR 14 (R 14 ) and -C 1~6 AlkylP(=O)(R 14 )2, each C 1~6 The alkyl may be one or more R 8 or R 12 and R 13が together form an optionally substituted heterocyclyl; Each R 14 However, independently, H, C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 alkyl-3- to 10-membered heterocyclyl, wherein each alkyl, alkenyl, alkynylcarbocyclyl, and heterocyclyl is selected from the group consisting of one or more R 8 is optionally replaced by [ka] But R M L in equation (1) 2 represents the bond that attaches r is 0 or 1, and m is 1-3.

[0338] 4.R M However, the equations (M-1Ai)~(M-1Dii): [ka] (In the formula, R 12 and R 13 are each independently H, -C(=O)OR 14 , -C(=O)N(R 14 )2, -C 1~6 AlkylC(=O)OR 14 , -C 1~6 AlkylC(=O)N(R 14 )2, -P(=O)(OR 14 )2-P(=O)OR 14 (R 14 ), -P(=O)(R 14 )2, -C 1~6 AlkylP(=O)OR 14 (R 14 ) and -C 1~6 AlkylP(=O)(R 14 )2, wherein each C 1~6 The alkyl may be one or more R 8 or R 12 and R 13が together form an optionally substituted heterocyclyl; R 15 ~R 18 are each independently -C(=O)N(R 14 )2, -P(=O)(OR 14 )2, -P(=O)OR 14 (R 14 ), and -P(=O)(R 14 )2, [ka] But R M L in equation (1) 2represents the bond that attaches and r is 0 or 1.

[0339] 5.R 12 and R 13 are each independently —C(═O)OH or —C(═O)NH; R 15 ~R 18 are each independently -C(=O)NH, -P(=O)(OH), -P(=O)(OH)H, and -P(=O)(OH)OC 1~6 The compound of exemplary embodiment 4, wherein the aryl group is selected from the group consisting of alkyl.

[0340] 6.R M is a chelating moiety having the structure of formula (M-1E), [ka] But R M L in equation (1) 2 represents the bond that attaches [ka] In the formula, R 23 and R 24 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted; Or at least one R 23 and R 24 The compound of any one of Exemplary Embodiments 1-5, wherein: combined to form an optionally substituted 3-10 membered heterocyclyl.

[0341] 7.R M is a chelating moiety having a structure of formula (M-1F), [ka] But R M L in equation (1) 2 The compound of any one of exemplary embodiments 1-6, wherein the compound represents a bond attached to [ka]

[0342] 8.L 1 and L 2 each independently is uninterrupted, or -O-, -S-, -C(=O)-, or -C(=O)NR 3 -, -NR 3 -, -C(=O)O-, -C(=O)S-, -S(=O)2-, -N(R 3 )C(=S)N(R 3 )- and -N(R 3 )C(=O)N(R 3 )-, and one or more R 8 The compound of any one of Exemplary Embodiments 1-7, wherein R is an aliphatic linker group optionally substituted with R.

[0343] 9.L 1 is uninterrupted or interrupted by one or more groups selected from -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH- 1~20 alkyl-, and L 2 But -C 1~10 alkyl-, where each alkyl is one or more R 8 The compound of exemplary embodiment 8, optionally substituted with

[0344] 10.L 1 and L 2 each independently represents H, C 1~10 Alkyl, OC 1~10 Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C 1~10 Alkyl-3 to 10-membered carbocyclyl, C 1~10 Alkyl-3 to 10-membered heterocyclyl, -N(R9 )2, -C(=O)N(R 9 )2, -OR 9 , -OC(=O)R 9 , -C(=O)R 9 , -C(=O)OR 9 , and -N(R 9 )C(=O)R 9 and each C is optionally substituted with one or more groups selected from 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl are each independently selected from the group consisting of one or more R 10 The compound of exemplary embodiment 8 or exemplary embodiment 9, optionally substituted with:

[0345] 11.X 1 ~X 3 are each independently selected from the group consisting of: -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O)2-, -NHC(=S)NH-, and -NHC(=O)NH-.

[0346] 12.X 1 ~X 3 The compound of any one of Exemplary Embodiments 1-11, wherein each is —C(═O)NH—.

[0347] 13. The part -X in formula (1) 1 -L 1 -X 2 - Structure (L-1): -NHC(=O)-R 19 -C(=O)NH-R 20 -CH(COOH)-NH-C(=O)-* (L-1) (In the formula, * indicates R in formula (1). 1 indicates a bond attached to a carbon atom bearing R 19 and R 20 are each independently one or more R8 C optionally replaced with 1~20 The compound of any one of exemplary embodiments 1-12, wherein:

[0348] 14. The part -X in formula (1) 3 -L 2 - has the structure (L-2) or (L-3): -NHC(=O)-R 19 -CH(COOH)-* (L-2) -NHC(=O)-R 19 -* (L-3) (In the formula, * indicates R in formula (1). M 14. The compound of any one of Exemplary Embodiments 1-13, having a bond attached to

[0349] 15. -X in formula (1) 3 -L 2 -R M The compound of any one of exemplary embodiments 1-14, wherein is 2(R,S)-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetamido]-5-amidopentanoic acid.

[0350] 16.R 1 and R 2 The compound of any one of Exemplary Embodiments 1-15, wherein each is independently an optionally substituted alkylaryl or an optionally substituted alkylheteroaryl.

[0351] 17.R 1 and R 2 The compound of exemplary embodiment 16, wherein each is independently an optionally substituted alkylaryl.

[0352] 18.R 1 and R 2 The compound of exemplary embodiment 16 or exemplary embodiment 17, wherein each is independently an optionally substituted benzyl.

[0353] 19.R 1 and R 2 are each independently H, halogen, C 1~10 Alkyl, OC 1~10 Alkyl, C 1~10 Haloalkyl, OC 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, OC 2~10 Alkenyl, OC 2~10 Alkynyl, -NO2, -N(R 11 )2, -CN, -SCN, -N3, =O, -C(=O)R 11 , -C(=O)OR 11 , -N(R 11 )C(=O)R 11 , and -OR 11 The compound of any one of Exemplary Embodiments 16-18, optionally substituted with one or more groups selected from:

[0354] 20.A is the formula (A-2): [ka] (In the formula, [ka] A is X in equation (1). 1 represents the bond that attaches R 21 is one or more R 8 C optionally replaced with 1~20 20. The compound of any one of Exemplary Embodiments 1-19, which is a PSMA-targeting ligand having the structure:

[0355] 21. The compound of any one of exemplary embodiments 1-20, wherein the compound of formula (1) is: [ka]

[0356] 22. A compound of formula (1) [ka] The compound of any one of exemplary embodiments 1-21, selected from the group consisting of:

[0357] 23.R M The compound of any one of Exemplary Embodiments 1-22, wherein is conjugated to a radioisotope.

[0358] 24. A radioactive isotope is 44 Sc, 47 Sc, 51 Mn, 52m Mn, 52g Mn, 55 Co, 58 Co, 58m Co, 61 Co, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 68 Ga, 86 Y, 90 Y, 89 Zr, 111 In, 134 La, 152 EU, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 177 Lu, 203 Pb, 211 Pb, 212 Pb, 212 Bi, 213 Bi, 225 Ac, and 227 The compound of exemplary embodiment 23, wherein the compound is selected from the group consisting of Th.

[0359] 25. A radioactive isotope is 212 The compound of exemplary embodiment 23 or exemplary embodiment 24, wherein Pb.

[0360] 26. A compound according to any one of exemplary embodiments 1 to 25 for use in the diagnosis, treatment, and / or prevention of PSMA-expressing cancer.

[0361] 27. The compound according to exemplary embodiment 26, wherein the PSMA-expressing cancer is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC).

[0362] 28. A pharmaceutical composition comprising a compound according to any one of exemplary embodiments 1-27 and a pharmaceutically acceptable excipient.

[0363] 29. A method for treating and / or preventing PSMA-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of exemplary embodiments 1-27 or a pharmaceutical composition described in exemplary embodiment 28.

[0364] 30. Use of a compound according to any one of exemplary embodiments 1 to 27 or a pharmaceutical composition according to exemplary embodiment 28 for treating and / or preventing PSMA-expressing cancer.

[0365] 31. Use of a compound according to any one of exemplary embodiments 1 to 27 or a pharmaceutical composition according to exemplary embodiment 26 in the manufacture of a medicament for treating and / or preventing PSMA-expressing cancer.

[0366] 32. The method or use according to any one of exemplary embodiments 29 to 31, wherein the PSMA-expressing cancer is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC).

[0367] 33. An imaging agent comprising a compound according to any one of exemplary embodiments 1-27.

[0368] 34.R M 34. The imaging agent of Exemplary Embodiment 33, wherein is conjugated to a positron-emitting radioisotope or a gamma-emitting radioisotope.

[0369] 35. A positron-emitting radioisotope is 68 Ga, 64 Cu, 55 Co, and 8935. The imaging agent of exemplary embodiment 34, wherein the imaging agent is selected from the group consisting of Zr.

[0370] 36. A diagnostic composition comprising an imaging agent according to any one of exemplary embodiments 33-35 and a pharmaceutically acceptable excipient.

[0371] 37. A method for imaging tissue in a subject, comprising administering to the subject a diagnostically effective amount of an imaging agent described in any one of exemplary embodiments 33-35 or a diagnostic composition described in exemplary embodiment 36.

[0372] 38. Use of an imaging agent according to any one of exemplary embodiments 33 to 35 or a diagnostic composition according to exemplary embodiment 36 for imaging tissue in a subject.

[0373] 39. An ex vivo method of imaging a tissue sample, comprising a diagnostically effective amount of the imaging agent of any one of exemplary embodiments 33-35 or the diagnostic composition of exemplary embodiment 36.

[0374] 40. Use of a compound according to any one of exemplary embodiments 1 to 27, or a pharmaceutical composition according to exemplary embodiment 26, in the manufacture of an imaging agent for imaging tissue in a subject.

[0375] 41. The method or use according to any one of exemplary embodiments 37 to 40, wherein the tissue is a PSMA-expressing tumor tissue.

[0376] 42. The method or use according to exemplary embodiment 41, wherein the PSMA-expressing tumor tissue is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC). [Example]

[0377] In order that the present disclosure may be more clearly understood, certain embodiments of the invention are described in further detail below by reference to the following non-limiting experimental materials, methodologies, and examples.

[0378] General Materials and Methods Fmoc-(9-fluorenylmethoxycarbonyl) amino acids, resins, and cyclen were purchased from Chem-Impex International (Illinois, USA). All other reagents and solvents were purchased from Sigma-Aldrich or ChemPep (China). The chelator DO3AM was purchased from Chematech (Dijon, France). Analytical reversed-phase high-performance liquid chromatography (RP-HPLC) was performed on a Phenomonex Jupiter® Proteo C18 (4 μm, 90 Å, 150 × 4.6 mm) column using a Shimadzu Prominence HPLC. Peptides were eluted with different gradients of 0.1% (v / v) trifluoroacetic acid (TFA) in HO (solvent A) and 0.1% TFA in acetonitrile (solvent B). HPLC-UV detection was performed at 220 nm and 254 nm. For radioactivity detection, a PMT / NaI(Tl) counter was connected to a Shimadzu Prominence HPLC. ESI mass spectra were acquired on a Varian 500-MS IT mass spectrometer (Agilent Technologies, Santa Clara, USA), and NMR spectra were obtained using a Varian 500 MHz Inova.

[0379] Example 1: Synthesis of 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazaicyclododecan-1-yl)pentanoic acid (pent(OtBu)-DOAM) DO3AM 1 (100 mg, 0.29 mmol, 1.0 equiv.), bromide 2 (110 mg, 0.32 mmol, 1.1 equiv.), and K2CO3 (40 mg, 0.79 mmol, 2.0 equiv.) in DMF (1 mL) were stirred overnight. The solution was filtered to remove insoluble salts, and the filtrate was concentrated in vacuo. The residue was purified by semi-preparative HPLC to give a yellow gum (60 mg). Benzyl-protected pent(OtBu)-DO3AM was purified by ESI-MS (M+H). +) was confirmed as 619.7, and the purity by UV-HPLC was >98%. 20% Pd / C (20% w / w, 10 mg) was suspended in a stirred solution of Pent(OtBu)-DO3AM-OBn (50 mg, 0.08 mmol, 1 equiv.) in methanol (5 mL) under a hydrogen atmosphere. The solution was stirred for 4 h and carefully filtered to remove the Pd / C. The residue was concentrated in vacuo to give the title compound (22 mg, 51%). 1 H NMR (D2O / CD3OD, 500MHz): δ4.84(s,6H), 3.71-3.43(m,2H), 3.35(s,16H), 3.30-3.30(s,1H), 2.39-2.29(m,2H), 1.49(s,9H). 1 H NMR (D2O / CD3OD, 125MHz): δ83.26, 57.86, 56.87, 54.17, 53.76, 52.45, 49.85, 33.80, 28.53, 28.41.

[0380] Example 2: Synthesis of ADVC001 With respect to the following examples and compounds of formula (1), a non-limiting illustration of the overall synthesis used to obtain compound ADVC001 is provided below as Scheme 1. [ka] Scheme 1 (reagents and conditions): a) K2CO3, DMF; b) i) suberic acid, HBTU, DIPEA, DMF, ii) Fmoc-D-Lys-OtBu.HCl, HBTU, DIPEA, DMF, iii) 20% piperidine, DMF, iv) Fmoc-D-Phe-OH, HBTU, DIPEA, DMF, iii) 20% piperidine, DMF, iv) Fmoc-3-Iodo-D-Tyr-OH, HBTU, DIPEA, DMF; c) i) 3, HBTU, DIPEA, DMF, ii) 88:2:5:5 TFA / TIPS / DTT / H2O, d) [ 212 Pb]PbCl2, NaOAc (pH 5.5).

[0381] The solid-phase synthesis of the peptidomimetic glutamate-urea-lysine linking motif is summarized in Scheme 1. Subsequent linker coupling followed standard fluorenylmethoxycarbonyl (Fmoc) protocols (Wellings et al., Methods in Enzymology, 1997, 289, 44-67, incorporated herein by reference) and the reported compound 4 (Benesova et al. al., J. Med. Chem. 2016, 59, 5, 1761-1775 (incorporated herein by reference). Finally, conjugation of the Pent(OtBu)-DO3AM chelator (Scheme 1) was achieved using HATU activation in the presence of DIPEA in DMF on the resin. Final cleavage, deprotection, and deprotection were achieved with a TFA / TIPS / HO / DTT mixture. The crude peptide conjugate was purified by HPLC and lyophilized to yield a white powder. The purity of ADVC001 was 98.6% by HPLC (Rt = 4.6 min, 18% solvent B for 5 min, 40% solvent B for 6 min) and as the HCl salt. The calculated mass (C 63 H 95 IN 14 O 20 )=1494.6, measured m / z[M+H + ]:1495.1.

[0382] Example 2.1: Alternative synthesis of unconjugated ADVC001 For the following examples and compounds of formula (1), a non-limiting illustration of an alternative overall synthesis used to obtain ADVC001 in unconjugated form is provided below as Scheme 2. [ka] Scheme 2 (reagents and conditions): a) K2CO3, DMF; b) i) HL-Glu(OtBu)-OtBu.HCl, CDI, DMF; ii) 3% hydrazine, iii) suberic acid, OxymaPure®, DIC, DMF, iv) Fmoc-D-Lys-OtBu.HCl, PyBOP, DIPEA, DMF, v) 20% piperidine, DMF, vi) Fmoc-D-Phe-OH, HBTU, DIPEA, DMF, vii) 20% piperidine in DMF, then Fmoc-3-iodo-D-Tyr-OH, OxymaPure®, DIC, DMF; c) i) 20% piperidine in DMF, then 3, HATU, DIPEA, DMF; ii) 92.5:5:2.5 TFA / HO / TIPS.

[0383] HL-Lys(Dde)-2-chloro-trityl-functionalized polystyrene resin (either 0.26 mmol / g or 0.59 mmol / g) was swollen in DMF for 30–120 min, after which the DMF was drained. A solution of HL-Glu(OtBu)-OtBu.HCl (2 equiv.) was dissolved in DMF using sonication, and 1,1-carbonyldiimidazole (2 equiv.) was added. This solution was transferred to the resin and stirred periodically for 16–24 h. The resin was drained and washed with DMF. This was followed by selective removal of the Dde protecting group with a solution of 3% hydrazine in DMF. The resin was drained, washed with DMF, and a solution of suberic acid (5 equiv.), ethyl cyano(hydroxyimino)acetate (10 equiv., also known as OxymaPure®), and DIC (10 equiv.) in DMF was added. The resin was stirred for 24 hours, drained, and rinsed with DMF. A solution of Fmoc-D-Lys-OtBu.HCl (2 equivalents), PyBOP (2 equivalents), and DIPEA (4 equivalents) in DMF was added to the resin and stirred periodically for 24 hours. The resin was again drained and washed with DMF, and the exposed Fmoc groups were removed using 20% piperidine in DMF, followed by washing with DMF. The resin was treated with a solution of Fmoc-D-Phe-OH (2 equivalents), HBTU (2 equivalents), and DIPEA (4 equivalents) in DMF for 24 hours with periodic stirring (complete coupling was achieved after 2 hours), followed by Fmoc deprotection using 20% piperidine, followed by rinsing with DMF. A solution of Fmoc-3-iodo-D-Tyr-OH (2 equivalents), ethyl cyano(hydroxyimino)acetate (2 equivalents), and DIC (4 equivalents) in DMF was added to the resin, and the resin was periodically agitated for 24 hours (complete coupling was achieved after 2 hours). The remaining Fmoc groups were removed using 20% piperidine, and the resin was rinsed with DMF. A solution of Pent(OtBu)-DO3AM (2 equivalents), HATU (6 equivalents), and DIPEA (4 equivalents) in DMF was added to the resin, and the resin was periodically agitated until the reaction was complete, as determined by ninhydrin testing at regular intervals (approximately every 10 minutes). The resin was washed with DMF, DCM, and diethyl ether.Peptide cleavage and deprotection were achieved using a 92.5:5:2.5 mixture of TFA / HO / TIPS for at least 16 hours. The crude peptide conjugate was precipitated with diethyl ether, separated by centrifugation, and purified by preparative TFA-based HPLC on reversed-phase C18 silica (eluent A: 0.1% TFA / Milli-Q water; eluent B: 0.1% TFA / 50% CH3CN / Milli-Q water; gradient: 20% B held for 20 minutes, then 20–70% B over 75 minutes) and lyophilized to yield a white powder. The purified peptide conjugate was dissolved at a concentration of 1 mg / mL in 2 mM HCl in 25% ACN / Milli-Q water, filtered through a sterile disposable 0.22 micron filter, and lyophilized for at least 24 hours. The purity of ADVC001 was 98.6% by HPLC (Rt=4.6 min, 18% solvent B for 5 min, 40% solvent B for 6 min) and as the HCl salt. Calculated mass (C. 63 H 95 IN 14 O 20 )=1494.6, measured m / z[M+H + ]:1495.1.

[0384] Example 3: 212 Radiolabeling of ADVC001 with Pb [ 212 A solution of [Pb]PbCl2 was buffered with 0.25 M NaOAc to a pH of 5.0-6.0, as determined by pH strips. A freshly prepared solution of ADVC001 in 0.25 M NaOAc (20 μL, 1 mg / mL) was added to the radioactive solution, and the resulting reaction mixture was allowed to stand at ambient temperature for 30 minutes or until the reaction was complete. The reaction was monitored using iTLC developed with 25 mM EDTA (pH 5.0) (unbound). 212 Pb R f >0.7, combine 212 Pb R f <0.3). Sodium ascorbate (100 mg / mL) was added to the reaction mixture. nat Radiochemical identity was confirmed against a Pb standard (Rt = 4.83 min, 18% solvent B for 5 min, 40% solvent B for 6 min) and radiochemical purity was >90%.

[0385] Example 4: 212 Biodistribution of Pb]Pb-ADVC001 Using an animal model of prostate cancer, 212 In vivo biodistribution studies of [Pb]Pb-ADVC001 were performed. 6 After inoculation of PC3-PIP (PSMA-expressing) and PC3 (PSMA-deficient) cell lines, tumor xenografts were grown on opposite flanks of male BALB / c nude mice. In this model, PC3 tumors were characterized by the intratumoral expression of PSMA. 212 [Pb]Pb serves as a control to assess the specificity of ADVC001 uptake. Once tumors reached a size of 5-10 mm, three groups of five mice (representing three different time points) were injected with 300-325 kBq [Pb]Pb via a lateral tail vein. 212 Mice were injected with [Pb]Pb-ADVC001. At 1, 4, and 24 hours after injection, mice were euthanized, and multiple organs were collected and weighed. Radioactivity in each organ was counted using a well-type gamma counter (counting window 218-258 keV). [%ID / g] was measured from each organ across the three time points. 212 The activity levels of [Pb]Pb-ADVC001 are shown in Table 1, and the biodistribution plot is shown in Figure 1A. Along with tumor uptake, [Pb]Pb in major organs (kidney, liver, and bone marrow) 212 Figure 3 shows the time-dependent accumulation of activity of [Pb]Pb-ADVC001. [Table 1]

[0386] [ 212A 24-hour in vivo biodistribution study of [Pb]Pb-ADVC001 revealed high specific uptake of the radiopharmaceutical in PSMA-positive tumors, with very low uptake in other organs, including control tumor sites. The drug is rapidly cleared from the body, as evidenced by a significant decrease in activity in the kidney over 24 hours. The activity ratios in PSMA-expressing tumors to PSMA-deficient tumors were 44.9, 18.5, and 170.8 at 1, 4, and 24 hours, respectively. These results demonstrate the significant uptake of [Pb]Pb-ADVC001 in PSMA-expressing tumors, with minimal binding in the kidney. 212 Pb]Pb-ADVC001.

[0387] Example 7: 212 Pb]Pb-PSMA I&T compared with 212 Biodistribution of Pb]Pb-ADVC001 [ 212 Pb]Pb-ADVC001 instead of [ 212 The biodistribution study of Example 7 was repeated using {Pb}-PSMA-I&T. The [%ID / g] values, expressed as percent injected dose / gram of tissue (%ID / g), were measured from each organ over three time points. 212 The biodistribution of [Pb]Pb-PSMA-I&T is shown in Figure 1B. Figure 2A shows the [Pb]Pb-PSMA-I&T distribution in each organ 4 hours after injection. 212 Pb]Pb-ADVC001 and [ 212 Pb]Pb-PSMA-I&T.

[0388] The tumor-to-kidney activity ratio provides a measure to compare the uptake and clearance of different radiopharmaceuticals in relevant animal models. 212 Pb]Pb-ADVC001 and [ 212 The tumor-to-kidney activity ratios of [Pb]Pb-PSMA-I&T are summarized in Figure 2B. 212 Pb]Pb-ADVC001 is 212 Pb]Pb-PSMA-I&T exhibited significantly higher tumor-to-kidney activity ratios across all time points.

[0389] Overall, [ 212 Pb]Pb-ADVC001 is 212 Compared to [Pb]Pb-PSMA I&T, [Pb]Pb-PSMA I&T shows high uptake and retention in PSMA-positive tumor tissues with very fast systemic and renal clearance and minimal retention in kidney tissue. This surprising result highlights the potential of [Pb]Pb as a radiopharmaceutical for the treatment of PSMA-expressing cancers, as high uptake and retention in the kidney can lead to damage and subsequent nephrotoxicity, limiting the administrable dose and ultimately the efficacy of the treatment. 212 Based on biodistribution data, [Pb]Pb-ADVC001 demonstrates its usefulness. 212 Pb]Pb-ADVC001 is 212 Pb]Pb-PSMA-I&T is expected to be a more effective treatment.

[0390] Example 8: 212 Dosimetry of Pb]Pb-ADVC001 Dosimetry estimates in animal model organs were calculated using the Organ-Level Internal Dose Assessment (OLINDA) method, which is recognized by the FDA for dosimetry modeling (Stabin, M. et al., OLINDA / EXM: The Second-Generation Personal Computer Software for Internal Dose Assessment in Nuclear Medicine). Activity levels were fitted using an exponential function to derive time-integrated activity coefficients (TIACs), which represent the area under the time-activity curve or absorbed dose for each organ. Organ weights and 212 The internal dose (mSv / MBq) was calculated based on the radiation emission profile of Pb. In this case, all daughter nuclides ( 212 Pb, 212 Bi, 212 Po and 208 The doses from the 1000 rTl were summed to obtain the dose estimates for each organ shown in Table 2. 212 Biodistribution data derived for [Pb]Pb-ADVC001 identified the kidney as the organ at highest risk for radiation damage. 212The estimated kidney dose for Pb]Pb-ADVC001 was 0.04406 mSv / MBq. These highly favorable dose estimates are based on the [ 212 Pb]Pb-ADVC001 at 1 hour and 24 hours. 212 The mean percent injected dose per gram (%ID / g) of Pb]Pb-ADVC001 was 13.73 and 0.95, respectively. 212 These dose estimates derived for Pb]Pb-ADVC001 are highly favorable in terms of reduced risk to sensitive organs. [Table 2]

Claims

1. Formula (1L) 【Chemical 1】 (In the formula, n is 0 to 3; X ３ is absent or is —O—, —S—, —C(═O)—, —C(═O)NR ３ -, -NR ３ -, -C(=O)O-, -C(=O)S-, -S(=O) ２ -, -S(=O) ２ NR ３ -, -S(=O)NR ３ -, -OS (=O) ２ -, -N(R ３ ) C(=S)N(R ３ )- and -N(R ３ )C(=O)N(R ３ )- is selected from the group consisting of L ２ is absent or an uninterrupted or interrupted, optionally substituted aliphatic linker group; R １ and each R ２ is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl, each of which is optionally substituted; Each R ３ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl, each of which is optionally substituted, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; The compound, wherein said compound is optionally conjugated to a radioisotope.

2. X ３ is absent or is —O—, —S—, —C(═O)—, —C(═O)NR ３ -, -NR ３ -, -C(=O)O-, -C(=O)S-, -S(=O) ２ -, -S(=O) ２ NR ３ -, -S(=O)NR ３ -, -OS (=O) ２ -, -N(R ３ ) C(=S)N(R ３ )- and -N(R ３ )C(=O)N(R ３ )- is selected from the group consisting of L ２ is absent or not interrupted, or is —O—, —S—, —C(═O)—, —C(═O)NR ３ -, -NR ３ -, -C(=O)O-, -C(=O)S-, -S(=O) ２ -, -N(R ３ ) C(=S)N(R ３ )- and -N(R ３ )C(=O)N(R ３ )-; and R １ and each R ２ is independently selected from the group consisting of aryl, alkylaryl, heteroaryl, and alkylheteroaryl; Each R ３ is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, alkylcarbocyclyl, and alkylheterocyclyl; L ２ and R １ ~R ３ Each of the groups is one or more R ８ is optionally replaced by Each R ８ are independently H, halogen, C １～１０ Alkyl, OC １～１０ Alkyl, C １～１０ Haloalkyl, OC １～１０ Haloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, OC ２～１０ Alkenyl, OC ２～１０ Alkynyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C １～１０ alkyl-3 to 10-membered carbocyclyl, C １～１０ alkyl-3 to 10-membered heterocyclyl, —NO ２ , -CN, -SCN, -N ３ , =O, -N(R ９ ) ２ , -C(=O)N(R ９ ) ２ , -S(=O)N(R ９ ) ２ , -S(=O) ２ N (R ９ ) ２ , -OR ９ , -SR ９ , —OC(═O)R ９ , -C(=O)R ９ , -C(=O)OR ９ , -S(=O)R ９ , -S(=O) ２ R ９ , -S(=O)OR ９ , -S(=O) ２ OR ９ , -S(=O)(OR ９ ) ２ , -OS(=O)R ９ , -OS(=O) ２ R ９ , -OS(=O)OR ９ , -OS(=O) ２ OR ９ , -OS(=O)(OR ９ ) ２ , -N(R ９ ) C(=O)R ９ , -N(R ９ )S(=O)R ９ , -N(R ９ )C(=O)N(R ９ ) ２ , -N(R ９ ) S(=O) ２ R ９ , -P(=O)(OR ９ ) ２ , -P(=O)OR ９ (R ９ ), -P(=O)(R ９ ) ２ , -OP(=O)(OR ９ ) ２ , -OP(=O)OR ９ (R ９ ) and -OP(=O)(R ９ ) ２ and each C is selected from the group consisting of １～１０ Alkyl, C １～１０ Haloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl are each independently selected from the group consisting of one or more R １０ is optionally replaced by Each R ９ However, independently, H, C １～６ Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C １～６ alkyl-3 to 10-membered carbocyclyl, and C １～６ alkyl-3- to 10-membered heterocyclyl; １～６ Alkyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl may be one or more R １０ is optionally replaced by Each R １０ are independently H, halogen, or —NO ２ , -N(R １１ ) ２ , -CN, -SCN, -N ３ ,=O, -C(=O)R １１ , -C(=O)OR １１ , -C(=O)N(R １１ ) ２ , -N(R １１ ) C(=O)R １１ , -OR １１ , -P(=O)(OR １１ ) ２ , -P(=O)OR １１ (R １１ ), -P(=O)(R １１ ) ２ , C １～６ Alkyl, and —OC １～６ is selected from the group consisting of alkyl, Each R １１ However, independently, H, C １～１０ Alkyl, C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C １～１０ alkyl-3 to 10-membered carbocyclyl, C １～１０ The compound of claim 1, wherein the heterocyclyl is selected from the group consisting of alkyl-3- to 10-membered heterocyclyl.

3. L ２ But C １～１０ Alkyl- or -C ２～１０ alkyl-, and each alkyl is independently one or more R ８ 2. The compound of claim 1, optionally substituted with

4. L ２ But C １～１０ Alkyl, OC １～１０ Alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, C １～１０ alkyl-3 to 10-membered carbocyclyl, C １～１０ alkyl-3 to 10-membered heterocyclyl, —N(R ９ ) ２ , -C(=O)N(R ９ ) ２ , -OR ９ , —OC(═O)R ９ , -C(=O)R ９ , -C(=O)OR ９ , and −N(R ９ ) C(=O)R ９ and each C is optionally substituted with one or more groups selected from １～１０ Alkyl, C １～１０ Haloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, 3- to 10-membered carbocyclyl, and 3- to 10-membered heterocyclyl are each independently selected from the group consisting of one or more R １０ 2. The compound of claim 1, optionally substituted with

5. L ２ But C １～１０ Alkyl, OC １～１０ Alkyl, —NH ２ , —OH, —COOH, and —C(═O)OC １～６ 10. The compound of claim 1, optionally substituted with one or more groups selected from alkyl.

6. X ３ is -O-, -S-, -C(=O)-, -C(=O)NH-, -NH-, -C(=O)O-, -C(=O)S-, -S(=O) ２ 2. The compound of claim 1, wherein the compound is selected from the group consisting of -, -NHC(=S)NH-, and -NHC(=O)NH-.

7. X ３ The compound of claim 1, wherein is -C(=O)NH-.

8. The moiety -X in formula (1L) ３ -L ２ is structure (L-2) or (L-3): -NHC(=O)-R １９ -CH(COOH)-* (L-2) -NHC(=O)-R １９ -* (L-3) (In the formula, R １９ is one or more R ８ C optionally substituted with １～１０ Alkyl or C ２～１０ is alkyl, The compound of claim 1, wherein * denotes a bond attached to the ring N in formula (1L).

9. The moiety -X in formula (1L) ３ -L ２ - is structure (L-2): -NHC(=O)-R １９ -CH(COOH)-* (L-2) (In the formula, R １９ is one or more R ８ C optionally substituted with １～１０ Alkyl or C ２～１０ is alkyl, The compound of claim 1, wherein * denotes a bond attached to the ring N in formula (1L).

10. R １ and R ２ 10. The compound of claim 1, wherein each independently is an optionally substituted alkylaryl or an optionally substituted alkylheteroaryl.

11. R １ and R ２ 11. The compound of claim 10, wherein each independently is an optionally substituted alkylaryl.

12. R １ and R ２ 12. The compound of claim 10 or 11, wherein each independently is optionally substituted benzyl.

13. R １ and R ２ each independently represents a halogen, C １～１０ Alkyl, OC １～１０ Alkyl, C １～１０ Haloalkyl, OC １～１０ Haloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, OC ２～１０ Alkenyl, OC ２～１０ Alkynyl, —NO ２ , -N(R １１ ) ２ , -CN, -SCN, -N ３ ,=O, -C(=O)R １１ , -C(=O)OR １１ , -N(R １１ ) C(=O)R １１ , and -OR １１ 12. The compound of claim 11, optionally substituted with one or more groups selected from:

14. R １ and R ２ each independently represents a halogen, —NO ２ , -NH ２ 12. The compound of claim 11, wherein the compound is benzyl optionally substituted with one or more groups selected from -CN, -SCN, -COOH and -OH.

15. R １ is benzyl, and R ２ But halogen, -NO ２ , -NH ２ , -CN, -SCN, -COOH, and -OH.

16. The compound of formula (1L) 【Chemistry 2】 2. The compound of claim 1, wherein:

17. The compound of formula (1L) 【Chemistry 3】 2. The compound of claim 1 selected from the group consisting of:

18. The compound of claim 1 , wherein the compound is conjugated to a radioisotope.

19. The radioisotope is ４４ Sc, ４７ Sc, ５１ Mn, ５２ｍ Mn, ５２ｇ Mn, ５５ Co, ５８ Co, ５８ｍ Co, ６１ Co, ６１ Cu, ６２ Cu, ６４ Cu, ６７ Cu, ６８ Ga, ８６ Y. ９０ Y. ８９ Zr, １１１ In, １３４ La, １５２ EU, １４９ Tb, １５２ Tb, １５５ Tb, １６１ Tb, １７７ Lu, ２０３ Pb, ２１１ Pb, ２１２ Pb, ２１２ Bi, ２１３ Bi, ２２５ Ac, and ２２７ 19. The compound of claim 18, wherein the compound is selected from the group consisting of Th.

20. The radioisotope is ２１２ 19. The compound of claim 18, wherein Pb.

21. 10. The compound of claim 1 for use in the diagnosis, treatment, and / or prevention of PSMA-expressing cancer.

22. 22. The compound of claim 21, wherein the PSMA-expressing cancer is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC).

23. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

24. A method for treating and / or preventing PSMA-expressing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in claim 1 or a pharmaceutical composition described in claim 23.

25. 24. Use of a compound of claim 1 or a pharmaceutical composition of claim 23 for treating and / or preventing PSMA-expressing cancer.

26. 24. Use of a compound of claim 1 or a pharmaceutical composition of claim 23 in the manufacture of a medicament for treating and / or preventing PSMA-expressing cancer.

27. 25. The method of claim 24, wherein the PSMA-expressing cancer is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC).

28. An imaging agent comprising the compound of claim 1.

29. 29. The imaging agent of claim 28, wherein the compound is conjugated to a positron-emitting or gamma-emitting radioisotope.

30. The positron-emitting radioisotope is ６８ Ga, ６４ Cu, ５５ Co, and ８９ 30. The imaging agent of claim 29, wherein the imaging agent is selected from the group consisting of Zr.

31. 30. A diagnostic composition comprising the imaging agent of claim 28 and a pharmaceutically acceptable excipient.

32. 32. A method for imaging tissue in a subject, comprising administering to the subject a diagnostically effective amount of the imaging agent of any one of claims 28 to 30 or the diagnostic composition of claim 31.

33. 32. Use of the imaging agent of claim 28 or the diagnostic composition of claim 31 for imaging tissue in a subject.

34. 32. An ex vivo method of imaging a tissue sample comprising a diagnostically effective amount of the imaging agent of claim 28 or the diagnostic composition of claim 31.

35. 24. Use of a compound of claim 1 or a pharmaceutical composition of claim 23 in the manufacture of an imaging agent for imaging tissue in a subject.

36. 33. The method of claim 32, wherein the tissue is a PSMA-expressing tumor tissue.

37. 37. The method of claim 36, wherein the PSMA-expressing tumor tissue is prostate cancer, preferably metastatic castration-resistant prostate cancer (mCRPC).

38. 10. A method for preparing a compound of claim 1, or a salt or solid-supported derivative thereof, comprising coupling a compound of formula (R-2) with a compound of formula (S-2): 【Chemistry 4】 (In the formula, RG １ and R.G. ２ are each independently a reactive coupling group. The method, wherein said compound of formula (S-2) is optionally attached to a solid support.

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